Zhanguo Su1*†
Lijuan Xiang2- 1Faculty of Physical Education, Huainan Normal University, Huainan, Anhui, China
- 2Chongqing Preschool Education College, Chongqing, China
The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.
1 Introduction
A growing worldwide health issue, neurodegenerative diseases affect millions and place great strain on people, families, and medical systems (Marques-Aleixo et al., 2021). These conditions are characterized by the progressive loss of neuronal structure and function, resulting in cognitive decline, it is increasingly recognized that their impact extends beyond the CNS to affect motor abilities and muscle health (Marques-Aleixo et al., 2021; de Lima et al., 2024; D’Angelo and Bresolin, 2006). Peripheral manifestations, particularly in skeletal muscle, are significant and involve substantially in the overall disease progression, reducing the quality of life and increasing morbidity in affected every person (Deldicque, 2013; Estébanez et al., 2018). This systemic impact suggests that therapeutic strategies should not solely focus on the neurological aspects but also consider the peripheral components of these debilitating conditions.
ER stress is a critical cellular mechanism associated with the pathogenesis of various diseases, including neurodegenerative disorders (Afroze and Kumar, 2019). The ER, a vital organelle within cells, is essential for protein synthesis, folding, modification, and trafficking. Maintaining balance within the ER, is crucial for optimal cellular function, especially in dynamic tissues such as skeletal muscle (Deldicque, 2013; Bohnert et al., 2018). Skeletal muscle, constituting a significant portion of body mass, is critical for locomotion, posture maintenance, breathing, and whole-body metabolism (Deldicque, 2013; Argilés et al., 2016). Its ability to function correctly is paramount for overall health and the capacity to perform daily activities.
Exercise has emerged as a promising non-pharmacological intervention in the quest for effective treatments for neurodegenerative diseases, with the potential to modulate various cellular stress pathways, including ER stress (Santiago and Potashkin, 2023). As a systemic intervention, exercise holds the potential to address both the neurological and muscular components of these diseases by influencing key shared cellular stress mechanisms like ER stress. The paper presents a review of the role of exercise in modulating ER stress and its impact on muscle function in PD, AD, Huntington’s disease, and ALS. By synthesizing current research findings, this report seeks to illuminate potential therapeutic benefits and identify avenues for future interventions.
2 Understanding endoplasmic reticulum stress and muscle function
The Endoplasmic Reticulum (ER) is a dynamic network of membranes within eukaryotic cells, fulfilling diverse and critical functions. In muscle cells, this organelle exists in a specialized form known as the sarcoplasmic reticulum (SR) (Deldicque, 2013; Zhang et al., 2021). The ER/SR is central to muscle function, regulating both the calcium homeostasis required for contraction and the protein quality control (synthesis, folding, and trafficking) essential for muscle maintenance (Deldicque, 2013; Delmotte and Sieck, 2015). Due to this central role in proteostasis, the muscle ER/SR is highly susceptible to stress. For clarity and consistency with the broader literature on the unfolded protein response, this review will use the term ‘ER stress’ throughout, with the understanding that in the context of muscle, this refers to stress within the SR.
ER stress arises when the protein folding capacity of this organelle is exceeded due to the accumulation of misfolded or unfolded proteins within its lumen (Deldicque, 2013; Gregersen and Bross, 2010). This imbalance can arise from a variety of pathological and physiological insults particularly relevant to skeletal muscle, including oxidative stress, hypoxia, nutrient excess (e.g., high-fat diet-induced lipotoxicity), systemic inflammation, calcium dysregulation, muscle disuse or denervation, and the accumulation of misfolded proteins associated with aging and specific disease states (Afroze and Kumar, 2019; Rotariu et al., 2022). The presence of these stressors impairs the ER’s capacity to correctly fold and process proteins, thereby activating a highly conserved intracellular signaling network referred to as the UPR (Afroze and Kumar, 2019; Schröder and Kaufman, 2005).
The UPR is a complex adaptive mechanism that is designed to restore homeostasis in the ER (Afroze and Kumar, 2019; Coleman and Haller, 2019). It does this by modulating protein synthesis to reduce ER load, upregulating ER chaperone expression to aid protein folding, and increasing misfolded protein degradation through ERAD pathways (Afroze and Kumar, 2019; Nishikawa et al., 2005). PERK, IRE1α, and ATF6 are the main ER transmembrane sensors that mediate the UPR (Deldicque, 2013; Siwecka et al., 2019; Fang et al., 2022). These sensors activate specific downstream signaling pathways that together function to mitigate ER stress.
While the UPR is initially a protective response, chronic ER stress leads to detrimental consequences for skeletal muscle. Extended activation of the UPR transitions from an adaptive to a maladaptive response, directly promoting muscle pathology through several mechanisms (Deldicque, 2013; Cirone, 2021). First, prolonged activation of the PERK and IRE1α pathways can trigger apoptosis in myocytes, notably through the upregulation of the pro-apoptotic transcription factor CHOP (Tabas and Ron, 2011; Kadowaki and Nishitoh, 2013). This leads to a loss of muscle fibers and contributes directly to atrophy. Second, the UPR can initiate potent inflammatory pathways, such as NF-κB signaling, leading to the production of cytokines that impair insulin sensitivity and promote protein degradation (Saaoud et al., 2024; Hotamisligil, 2010). Third, persistent phosphorylation of eIF2α by PERK, intended to reduce protein synthesis, can chronically suppress the translation of essential contractile proteins, further exacerbating muscle wasting and weakness. In the context of muscle, this combination of apoptosis, inflammation, and impaired protein synthesis manifests as muscle dysfunction, atrophy (loss of muscle mass), and weakness, impacting overall physical capacity (Lin et al., 2025; Gordon et al., 2013). It is critical to explicitly differentiate between an adaptive (physiological) UPR and a maladaptive (pathological) UPR. The adaptive response, often triggered by moderate exercise, is transient and aims to restore homeostasis. Its hallmarks are the temporary activation of the IRE1α and ATF6 pathways to increase the ER’s protein-folding capacity by upregulating chaperones like BiP and enhancing ERAD (Kaufman et al., 2010; Wu et al., 2011). In contrast, a maladaptive response occurs when the stress is too severe or prolonged, overwhelming the adaptive capacity. This state is characterized by the sustained activation of the PERK pathway, leading to chronic translational repression, and the strong upregulation of the pro-apoptotic transcription factor CHOP, which ultimately triggers inflammation and cell death (Sano and Reed, 2013; Yang et al., 2017). The goal of therapeutic exercise is to consistently activate the adaptive UPR without tipping the balance into a maladaptive state.
Therefore, maintaining a delicate balance in ER function is paramount for overall muscle health. The UPR’s duality, acting as both a protector and a potential instigator of damage under prolonged stress, highlights the complexity of this cellular response (Figure 1).
Figure 1. UPR and ER stress in muscle health. Sarcoplasmic reticulum (SR) controls protein quality and calcium homeostasis in muscle cells. SR protein misfolding causes ER stress and UPR activation under stress conditions like oxidative stress or inflammation. The UPR functions through three pathways: PERK (reduces protein synthesis), IRE1α (enhances chaperone expression and ER degradation), and ATF6 (induces inflammatory and apoptotic responses). While initially protective, prolonged UPR activation causes muscle dysfunction, atrophy, and weakness. This figure provides a schematic summary of the canonical UPR pathways as they relate to skeletal muscle pathology, based on the literature reviewed herein.
3 The role of ER stress in specific neurodegenerative diseases and muscle dysfunction
A critical question in the pathophysiology of neurodegenerative diseases is how ER stress in the central nervous system (CNS) correlates with the ER stress observed in peripheral skeletal muscle. The connection is likely multifactorial rather than a single direct cause. One major mechanism is a parallel pathology driven by systemic factors; for instance, the widespread expression of mutant proteins (like mHTT in Huntington’s disease) or the presence of systemic inflammation and oxidative stress can independently induce ER stress in both neurons and muscle cells (Joshi et al., 2025; Kumar and Ratan, 2016; Cisbani and Cicchetti, 2012). A second mechanism involves an indirect, consequential link, where primary neurodegeneration in the CNS leads to secondary ER stress in the muscle. This can occur through processes like denervation, disuse atrophy, or altered neural signaling, all of which are potent triggers for muscle ER stress (Yadav and Dabur, 2024; Castelli et al., 2025). Finally, there may be a retrograde signaling component, where stressed or atrophying muscle releases inflammatory myokines that can cross the blood–brain barrier, potentially exacerbating neuroinflammation and neuronal ER stress (Rai and Demontis, 2022; Lee et al., 2021). Understanding these potential links is crucial for developing holistic therapeutic strategies that address both central and peripheral manifestations of these diseases (Figure 2).
Figure 2. Potential links between ER stress in the central nervous system (CNS) and skeletal muscle in neurodegenerative diseases. Three major mechanisms may explain the correlation between CNS and muscle ER stress: (i) Parallel pathology, where systemic factors such as mutant proteins, inflammation, and oxidative stress induce ER stress independently in both neurons and muscle; (ii) Indirect consequential link, where primary neurodegeneration leads to muscle denervation, disuse atrophy, and secondary ER stress; and (iii) Retrograde signaling, where atrophying muscle releases inflammatory myokines that can cross the blood–brain barrier and exacerbate neuroinflammation and neuronal ER stress. Together, these processes create a bidirectional interaction contributing to disease progression.
3.1 Parkinson’s disease (PD)
In Parkinson’s Disease (PD), ER stress is well-established as a pivotal element in the pathogenesis within the central nervous system (Baek et al., 2019). The primary neuropathology involves the loss of dopaminergic neurons, where the accumulation of misfolded alpha-synuclein directly triggers the UPR, compromises ER function, and contributes to a toxic cycle of protein misfolding and neuronal death (Li, 2023). The vast majority of mechanistic studies on ER stress in PD have been conducted in this neuronal context.
The focus on CNS pathology often overshadows peripheral manifestations; however, PD motor symptoms like muscle rigidity and bradykinesia point to significant muscle involvement (Kong et al., 2025; Palakurthi and Burugupally, 2019). The link to ER stress in muscle is twofold. First, it can be inferred as an indirect consequence of CNS pathology; impaired neuronal signaling and motor control can lead to disuse or altered muscle activity, which are known stressors (Bernard-Marissal et al., 2015; Paschen and Doutheil, 1999). Second, and more directly, emerging evidence now suggests a primary ER stress response within muscle tissue itself, although this research is less extensive than the CNS-focused work. Studies have begun to identify UPR activation in the muscle of PD models, suggesting that the cellular stress response is not confined to the brain (Deldicque, 2013; Zhang et al., 2015; Mercado et al., 2016). This distinction is critical: muscle dysfunction may not just be a downstream effect of neurodegeneration but also a parallel pathology.
3.2 Alzheimer’s disease (AD)
While the role of ER stress in the neurons of the AD brain is well-documented, its involvement in peripheral skeletal muscle is an area of active investigation rather than established fact. Patients with AD frequently experience significant physical decline, including muscle weakness and sarcopenia, that cannot be fully explained by cognitive impairment alone (Endres and Reinhardt, 2013; Uddin et al., 2020; Ekundayo et al., 2024). The link to ER stress in muscle is therefore largely inferred from the systemic nature of the disease. It is hypothesized that systemic factors present in AD, such as chronic inflammation or circulating amyloid-β oligomers, could induce a parallel ER stress response in muscle tissue, thereby contributing to the observed frailty (Deldicque, 2013; Burtscher et al., 2021). It is crucial to differentiate this hypothesis from the direct evidence seen in the CNS, where amyloid-β and tau aggregates are known to trigger the UPR (Li et al., 2015; Ajoolabady et al., 2022). Thus, while plausible, the contribution of muscle-specific ER stress to AD pathology requires more direct experimental validation.
3.3 Huntington’s disease (HD)
An expanded CAG repeat in the huntingtin gene produces a mHTT protein with an abnormally long polyglutamine stretch, causing HD, a progressive neurodegenerative disorder (Maity et al., 2022; Gil and Rego, 2008). The accumulation of this misfolded mHTT protein within neurons induces significant ER stress and disrupts ER homeostasis (Maity et al., 2022). ER stress contributes to neuronal dysfunction, ultimately resulting in the neuronal death observed in HD.
HD is characterized by a triad of symptoms: motor impairments, cognitive decline, and psychiatric disturbances. The motor impairments—including chorea, dystonia, and rigidity—are accompanied by significant muscle atrophy and weakness that contribute substantially to functional decline (Goh et al., 2018; Mehanna and Jankovic, 2024). While direct evidence for ER stress in the muscle of HD patients is still emerging, strong indirect evidence links the pathology to this pathway. The mutant huntingtin (mHTT) protein is expressed universally, including in muscle tissue, where it forms aggregates (Jodeiri Farshbaf and Ghaedi, 2017; Barron et al., 2021). The presence of these aggregates can directly overwhelm the muscle’s protein quality control systems, such as the ER-associated degradation (ERAD) pathway, a classic trigger for the UPR. Furthermore, muscle biopsies from HD models show significant mitochondrial dysfunction and impaired autophagy, pathologies mechanistically linked to chronic ER stress. A key element of this pathology is the disruption of ER-mitochondrial crosstalk; ER stress alters calcium signaling between the two organelles, which in turn cripples mitochondrial bioenergetics and promotes cell death in muscle fibers (Maity et al., 2022; Vidal et al., 2011; Volgyi et al., 2015). Therefore, it is highly plausible that mHTT accumulation in muscle fosters a state of chronic ER stress that drives intrinsic muscle wasting (Afroze and Kumar, 2019; Hassab et al., 2023). Given this systemic pathology, investigating ER stress in peripheral tissues like muscle could uncover vital therapeutic targets beyond the brain. Strategies aimed at alleviating ER stress or improving ERAD function hold promise for improving both neurological and muscular symptoms in this devastating disease (Maity et al., 2022; Lontay et al., 2020).
3.4 Amyotrophic lateral sclerosis (ALS)
ALS or Lou Gehrig’s disease, is a neurodegenerative disorder that is characterized by the selective degeneration of motor neurons in the brain and spinal cord. It is a condition that progresses rapidly and ultimately results in death (Duranti and Villa, 2023; Loeffler et al., 2016). This neuronal degeneration results in progressive muscle atrophy, weakness, and ultimately paralysis, culminating in respiratory failure (Tiryaki and Horak, 2014; Wijesekera and Leigh, 2009). ER stress affects motor neurons and skeletal muscle tissue, contributing to ALS (Zhao et al., 2022; Jeon et al., 2023).
In contrast to other neurodegenerative conditions where muscle pathology is often considered secondary or inferred from CNS dysfunction, ALS presents compelling direct evidence for ER stress as a primary event in skeletal muscle tissue (Loeffler et al., 2016).
In ALS, the buildup of misfolded proteins like mutant superoxide dismutase 1 (SOD1) and TDP-43 is a key pathological driver that directly induces ER stress in muscle. For example, mutant SOD1 is known to accumulate within the ER and on the outer mitochondrial membrane of muscle cells, where it physically disrupts protein folding machinery and impairs calcium homeostasis, leading to a robust UPR activation (Nagaraju et al., 2005; de Mena et al., 2021). Importantly, research in ALS animal models shows that markers of ER stress (e.g., CHOP, BiP) are upregulated in skeletal muscle during pre-symptomatic stages, before significant denervation occurs (Nagaraju et al., 2005; Chen et al., 2015). This early activation provides strong evidence that muscle is not a passive victim of motor neuron loss but rather a primary site of pathology, with intrinsic ER stress contributing directly to atrophy by disrupting protein translation and activating pro-apoptotic pathways (Nagaraju et al., 2005; Jesse et al., 2017; Galbiati et al., 2014). This muscle-centric pathology helps explain why the role of exercise in ALS is uniquely complex and controversial (de Almeida et al., 2012; Tsitkanou et al., 2019). While moderate activity may be beneficial, strenuous exercise is hypothesized to be detrimental by overwhelming already vulnerable motor neurons. This could occur through several mechanisms, including increased metabolic load, excitotoxicity at the neuromuscular junction, and heightened oxidative stress that the compromised neuron cannot buffer (Duranti and Villa, 2023; Siciliano et al., 2020; Dishman et al., 2006; Sheikh and Vissing, 2019; Dobrowolny et al., 2021). This potential for harm underscores that any therapeutic strategy, including exercise, must account for the primary pathology. Therefore, the strong evidence for muscle-intrinsic ER stress in ALS not only highlights a therapeutic target but also provides a rationale for extreme caution with exercise prescription, demanding highly individualized and carefully monitored programs (Table 1).
Table 1. Summary of ER stress markers in neurodegenerative diseases.
4 Exercise as a modulator of ER stress in skeletal muscle
4.1 Acute vs. chronic exercise
Physical exercise has a multifaceted impact on ER stress in skeletal muscle, with notable differences observed between acute and chronic exercise protocols (Petriz et al., 2017; Marafon et al., 2022). Acute exercise, including endurance and resistance activities, can trigger ER stress and activate the unfolded protein response in skeletal muscle (Bohnert et al., 2018; Egan and Sharples, 2023). This initial stress response is likely due to the increased protein synthesis demands and fluctuations in calcium levels that occur during muscle contraction (Berchtold et al., 2000; Kameyama and Etlinger, 1979). ER stress markers like BiP, CHOP, GRP94, and phosphorylated eIF2α have been found to increase in skeletal muscle after a single bout of intense exercise (Afroze and Kumar, 2019; Gallot and Bohnert, 2021; Khadir et al., 2016; Marafon, 2022). This suggests that the UPR activation following acute exercise could be an adaptive mechanism, preparing the muscle for future challenges.
Chronic regular moderate-intensity exercise induces adaptations that reduce the responses of genes and proteins associated with ER stress in skeletal muscle (Li et al., 2019; Korkmaz et al., 2023). This suggests that consistent exercise training can enhance the muscle’s ability to cope with cellular stress, potentially protecting it against subsequent stressors. However, it is crucial to note that excessive exercise intensity and volume, particularly without adequate rest and recovery, can have detrimental effects and may paradoxically increase ER stress, as observed in overtraining scenarios (Marafon et al., 2022; Pereira et al., 2016). The biphasic response of ER stress to exercise highlights the necessity of meticulously evaluating exercise prescription parameters, including intensity, duration, frequency, and rest periods, to achieve beneficial adaptations in ER health within skeletal muscle.
This distinction between the acute response and chronic adaptation can be visualized as a timeline (Figure 3). A single bout of exercise acts as a transient homeostatic challenge, causing a rapid increase in ROS and calcium flux that triggers a mild, short-lived UPR activation. This is a crucial signaling event that results in the temporary upregulation of protective chaperones and antioxidant enzymes. With consistent training over weeks and months, these repeated acute signals drive a long-term adaptive state. This chronic adaptation is characterized by an increased baseline pool of ER chaperones, greater mitochondrial efficiency, and enhanced antioxidant capacity (Hetz and Papa, 2018; Silva et al., 2022; Farrell and Turgeon, 2021). Consequently, the trained muscle exhibits lower basal ER stress and a blunted, more efficient UPR response when faced with subsequent stressors, signifying a more resilient cellular phenotype.
Figure 3. Acute versus chronic adaptations of exercise-induced ER stress responses. A single bout of exercise acts as a transient homeostatic challenge, increasing ROS and calcium flux, which triggers mild and short-lived UPR activation, upregulating protective chaperones and antioxidant enzymes (acute response). With consistent training, these repeated signals drive long-term adaptations, including elevated baseline ER chaperones, improved mitochondrial efficiency, and enhanced antioxidant capacity. Trained muscle thus exhibits lower basal ER stress and a blunted, more efficient UPR under stress, reflecting a resilient cellular phenotype.
4.2 Intensity and type of exercise
ER stress in skeletal muscle has been shown to be induced by both endurance (aerobic) and resistance exercise, although the specific markers and the extent of the response may vary depending on the type of exercise and the intensity of the exercise (Wang et al., 2011; Koulmann and Bigard, 2006). HIIT is emerged as a potentially beneficial exercise modality, with some studies indicating that it can lead to a decrease in ER stress markers within skeletal muscle (Kim et al., 2014; Liu et al., 2013). This finding challenges the notion that only moderate-intensity exercise is beneficial and suggests that higher intensity exercise, when appropriately managed, could trigger distinct adaptive pathways in the ER.
Regular moderate-intensity exercise appears to be generally beneficial for attenuating basal ER stress levels in skeletal muscle, promoting a more resilient cellular environment (de Sousa Fernandes et al., 2023; El Assar et al., 2022). In contrast, low-intensity exercise may be inadequate to produce notable alterations in ER stress markers, especially when conducted in a fasted condition (Marafon et al., 2022; Lee et al., 2015). Furthermore, it is important to consider that the response to exercise-induced ER stress can differ depending on the specific muscle being examined (de Sousa Fernandes et al., 2023; Kim et al., 2010; Kim et al., 2018). For instance, the soleus and EDL muscles may express different ER stress markers after the same exercise. This heterogeneity highlights the complexity of skeletal muscle and the need for tissue-specific considerations when designing exercise interventions aimed at modulating ER stress.
4.3 Molecular mechanisms of exercise-induced ER stress modulation
Several molecular mechanisms may explain how exercise modulates ER stress in skeletal muscle. PGC-1α, a key regulator of mitochondrial biogenesis and energy metabolism in muscle, is crucial for mediating exercise-induced adaptations (Afroze and Kumar, 2019; Baar, 2004; Feng et al., 2013; Lira et al., 2010). Research indicates that PGC-1α interacts with cleaved ATF6α, a transcription factor activated during the unfolded protein response (UPR), to promote an adaptive UPR in skeletal muscle post-exercise (Afroze and Kumar, 2019; Wu et al., 2011; Jung and Kim, 2014). This interaction indicates that PGC-1α is essential for ER stress adaptation in muscle, potentially improving ER health and resilience.
Exercise also increases the expression of ER chaperones, proteins that help protein folding and restore ER homeostasis, reducing ER stress (Deldicque, 2013). Interestingly, different UPR arms may play different roles in exercise adaptation. PERK/eIF2α/CHOP pathway may negatively regulate muscle homeostasis after exercise training, while the ATF6α pathway appears to be involved in adaptive response and recovery from exercise-induced damage (Afroze and Kumar, 2019; Ogborn, 2013; Chen et al., 2023; Vargas-Mendoza et al., 2019). For example, it is demonstrated that the deletion of CHOP genetic material leads to an enhancement of exercise adaptation in mice with skeletal muscle-specific PGC-1α knockout (Afroze and Kumar, 2019; Kristensen et al., 2018). Intracellular calcium level fluctuations during muscle contraction in exercise are considered a potential trigger for UPR activation (Afroze and Kumar, 2019; Ito et al., 2018; Kano et al., 2012). Additionally, Inflammation, especially with respect to the cytokine IL-6, may contribute to the intricate regulation of ER stress homeostasis during exercise (Marafon et al., 2022; Ropelle et al., 2010). The opposing roles of different UPR arms in exercise-induced muscle adaptation underscore the complexity of this cellular response and the need for targeted interventions that selectively modulate specific UPR pathways to maximize benefits (Figure 4). Table 2 summarizes what exercise does for ER stress in neurodegenerative diseases.
Figure 4. This diagram illustrates how exercise influences ER stress pathways in skeletal muscle. Key components include the activation of PGC-1α, which interacts with cleaved ATF6α to promote an adaptive UPR. Exercise also increases ER chaperones and induces fluctuations in intracellular calcium (Ca2+), which can trigger PERK pathway activation. While the PERK/eIF2α/CHOP axis may exert negative regulation, deletion of CHOP improves muscle adaptation. Additionally, IL-6-mediated inflammation contributes to ER stress modulation, highlighting the complexity and specificity of UPR pathway roles in exercise adaptation.
Table 2. ER stress markers in skeletal muscle (rodents) after exercise interventions.
4.4 The interconnected stress web: UPR, mitochondria, oxidative stress, and inflammation
The progression of muscle decline in neurodegenerative diseases is not driven by a single pathway but by a destructive interplay between several cellular stress responses. The UPR, mitochondrial dysfunction, oxidative stress, and inflammation form a self-perpetuating ‘vicious cycle.’ Understanding how exercise modulates ER stress requires appreciating its ability to intervene at multiple points within this interconnected web.
In a pathological state, these four elements amplify one another. Mitochondrial dysfunction is a central node; damaged mitochondria produce less ATP and leak excessive reactive oxygen species (ROS), causing oxidative stress. This surge in ROS directly damages lipids and proteins within the ER, impairing calcium handling and protein folding, which in turn triggers the UPR (Misrani et al., 2021; Kowalczyk et al., 2021). A chronically activated UPR then feeds back to harm the mitochondria. It disrupts the critical physical and functional connection at the mitochondria-associated membranes (MAMs), impairing calcium transfer needed for bioenergetics and activating mitochondria-mediated apoptosis through effectors like CHOP. Furthermore, the UPR, particularly via the IRE1α and PERK pathways, activates pro-inflammatory signaling cascades like NF-κB and JNK (Senft and Ronai, 2015; Bravo et al., 2012). The resulting chronic inflammation closes the loop by generating more ROS and directly impairing mitochondrial function, thus perpetuating a cycle of cellular damage, energy crisis, and muscle wasting.
Exercise is uniquely positioned to break this vicious cycle and foster a ‘virtuous cycle’ of cellular health.
• Mitochondrial Quality Control: Regular exercise is the most powerful physiological stimulus for mitochondrial biogenesis, driven by the master regulator PGC-1α. This process not only creates new, healthy mitochondria but also stimulates mitophagy, the selective removal of damaged ones. The result is a healthier mitochondrial pool that produces ATP efficiently with minimal ROS leakage, directly combatting the cycle’s origin (Memme and Hood, 2020; Memme et al., 2021; Kyriazis et al., 2022).
• Antioxidant Defenses: Chronic exercise upregulates the body’s endogenous antioxidant systems. It activates the Nrf2 transcription factor, which increases the expression of key antioxidant enzymes like superoxide dismutase (SOD) and catalase. This enhanced defensive capacity allows the muscle to better neutralize ROS, protecting the ER and other organelles from oxidative damage (Jomova et al., 2023; de Lemos et al., 2012).
• Adaptive UPR Preconditioning: As previously discussed, acute exercise induces a transient, physiological UPR. This response is not pathological but adaptive; it increases the expression of ER chaperones and enhances the ER’s folding capacity. This ‘preconditioning’ makes the ER more resilient to subsequent, more severe stressors, effectively raising the threshold for triggering a maladaptive UPR (Salminen et al., 2020).
• Systemic Anti-Inflammatory Effects: While acute exercise is pro-inflammatory, regular training has potent anti-inflammatory effects. It reduces chronic low-grade inflammation by decreasing visceral fat mass (a major source of inflammatory cytokines) and promoting the release of anti-inflammatory myokines from the muscle. This dampens the inflammatory signaling that would otherwise contribute to oxidative stress and mitochondrial damage (Flynn et al., 2007).
5 Exercise interventions and their effects on ER stress and muscle function in neurodegenerative diseases
While the primary focus of this review is on skeletal muscle, a comprehensive understanding of exercise’s therapeutic benefits requires acknowledging its profound effects on ER stress within the brain itself. Exercise combats neuronal ER stress through several interconnected mechanisms. First, it enhances cerebral proteostasis by upregulating the expression of molecular chaperones, such as heat shock proteins (HSPs), which improves the brain’s capacity to correctly fold proteins and clear toxic aggregates like amyloid-β and tau (Wankhede et al., 2022; Xu et al., 2022; Hu et al., 2022). Second, exercise robustly increases levels of Brain-Derived Neurotrophic Factor (BDNF), a critical neurotrophin that promotes neuronal survival and resilience against stressors, including ER stress-induced apoptosis (Wang and Holsinger, 2018). Third, physical activity exerts potent anti-inflammatory and antioxidant effects, reducing neuroinflammation and oxidative damage, both of which are primary triggers of the UPR in neurons (Simioni et al., 2018; Wang et al., 2023). Finally, by improving cerebral blood flow and promoting autophagy, exercise facilitates the efficient clearance of misfolded proteins, thereby alleviating the initial burden that would otherwise trigger an ER stress response (Gao et al., 2025; Li et al., 2024). These neuroprotective actions, combined with the peripheral effects on muscle, underscore the holistic therapeutic potential of exercise in combating neurodegenerative diseases.
5.1 Parkinson’s disease
According to the available evidence, individuals who suffer from PD may reap significant benefits from engaging in physical activity, particularly aerobic exercise and resistance training (Falvo et al., 2008; Schootemeijer et al., 2020). Regular physical activity improves motor function, reduces bradykinesia, and enhances balance and coordination, and ultimately improve the overall quality of life for PD patients (Duranti and Villa, 2024; Borrione et al., 2014). Exercise may benefit PD muscle function by improving muscle strength, mitochondrial function, and systemic inflammation (Duranti and Villa, 2024; Kelly et al., 2014). The findings indicate a beneficial effect of exercise on motor symptoms in PD; however, the specific influence of exercise interventions on ER stress markers in the muscle tissue of Parkinson’s patients or animal models is not clearly addressed in the provided excerpts. Considering the established function of ER stress in muscle dysfunction and the capacity of exercise to influence ER stress in healthy muscle, future research should explore this relationship to enhance understanding of the mechanisms that underlie the benefits of exercise in PD and to potentially refine exercise interventions for this demographic.
5.2 Alzheimer’s disease
Exercise training has demonstrated potential in mitigating cerebrovascular dysfunction associated with AD by influencing ER stress within the brain. Research indicates that physical activity can diminish the expression of abnormal ER stress markers in the brains of animal models of AD, specifically p-IRE1α, CHOP, and p-eIF2α (Hong et al., 2020; Lange-Asschenfeldt and Kojda, 2008; Medinas et al., 2021). This suggests that exercise can modulate ER stress-dependent endothelial dysfunction, which is linked to AD. Evidence suggests that exercise can improve cerebral blood flow, reducing amyloid-β accumulation, neuronal cell death, and cognitive decline in AD patients (Ribarič, 2022; Tan et al., 2021). While these findings highlight the neuroprotective effects of exercise in AD, research specifically examining the effects of exercise on ER stress within muscle tissue of AD models or patients and its potential contribution to improved physical function is less prominent in the provided snippets. Considering the possible association between ER stress and muscle atrophy in AD, further investigation into whether exercise also alleviates ER stress in muscle tissue in this context could provide a more complete understanding of its therapeutic benefits for both cognitive and physical function.
5.3 Huntington’s disease
The research snippets provided do not specifically examine the effects of exercise interventions on ER stress and muscle function in models or patients with HD. However, one snippet (Simha et al., 2025) mentions a case study where an Ayurvedic treatment regimen, including Sida cordifolia (SC), led to improvements in motor symptoms and a decrease in ER stress in a model of HD (Simha et al., 2023; Tung et al., 2025). This suggests that interventions targeting ER stress might have the potential to improve motor function in HD. Given the contribution of ER stress in HD neuronal pathology and the evidence for mHTT expression in peripheral tissues, including muscle, more research on the effects of exercise on ER stress and muscle function is needed. Such studies may help manage this disease’s debilitating motor symptoms.
The lack of evidence for exercise interventions in HD is also due to significant practical challenges. The characteristic motor symptoms of HD, such as chorea (involuntary movements) and dystonia, make the implementation and standardization of exercise protocols extremely difficult. This creates barriers to conducting the rigorous clinical trials needed to assess both functional outcomes and underlying molecular changes like ER stress.
5.4 Amyotrophic lateral sclerosis
The impact of exercise in ALS is multifaceted and has been a topic of ongoing discussion (Chen et al., 2008). Some studies indicate that exercise may enhance the quality of life for individuals with ALS, others indicate potential negative outcomes, particularly with strenuous exercise, possibly due to increased metabolic demands on already compromised motor neurons and muscle (Duranti and Villa, 2023; de Almeida et al., 2012). Snippet (Chen et al., 2015) mentions that exercise is proved to upregulate ER stress sensors and ER chaperones in skeletal muscle, but it does not specify whether this occurs in the context of ALS. Snippets (Deldicque, 2013; Gallot and Bohnert, 2021) discuss how exercise affects muscle ER stress, which might be relevant to understanding the potential impact in ALS. However, there is a lack of direct evidence within the provided snippets regarding whether exercise interventions specifically modulate ER stress markers in the muscle tissue of ALS models or patients. The conflicting evidence surrounding exercise in ALS underscores the critical need for highly individualized and carefully monitored exercise programs for individuals with this condition. Future research should aim to elucidate how different exercise regimens affect ER stress in muscle in ALS, which could help in developing safer and more effective exercise guidelines for this vulnerable population (Tables 1, 2, Figure 5).
Figure 5. Exercise effects on ER stress and muscle function.
5.5 Caveats and controversies: the double-edged sword of exercise
While this review highlights the therapeutic potential of exercise, it is crucial to acknowledge that its effects are not universally positive and the literature contains significant contradictory evidence, particularly for ALS. The concept of hormesis is central: while moderate stress can be adaptive, excessive stress can be damaging, and this balance is especially delicate in neurodegenerative diseases.
The controversy is most pronounced in ALS, where some studies have even suggested a link between elite athletic activity and an increased risk of developing the disease (Hu and Robertson, 2020; Chapman et al., 2023). Furthermore, preclinical studies in SOD1 mutant mouse models have shown conflicting results based on exercise intensity. While moderate, voluntary wheel running has sometimes shown modest benefits or no effect, forced, high-intensity exercise (such as forced treadmill running or swimming) has been demonstrated to accelerate disease onset, worsen motor neuron loss, and shorten lifespan (Hu and Robertson, 2020; Scaricamazza et al., 2024; Manzanares et al., 2018). These negative outcomes are thought to result from exacerbating the underlying pathology, including overwhelming cellular bioenergetics and increasing oxidative stress on already vulnerable motor neurons.
This “double-edged sword” concept, while most stark in ALS, is relevant across all neurodegenerative diseases. In advanced stages of PD or AD, for instance, high-intensity exercise could increase the risk of falls, injury, or adverse cardiovascular events (Berg and Cassells, 1992; Ernst et al., 2023). Therefore, the key takeaway is that the intensity, duration, and type of exercise are critical variables that determine whether the outcome is beneficial or detrimental. Future research must move beyond simply asking if exercise is helpful and focus on defining precise, safe, and effective exercise prescriptions tailored to the specific disease, its stage, and the individual patient’s capacity.
6 Conclusion and future directions
In conclusion, Endoplasmic Reticulum (ER) stress is a significant contributor to the pathogenesis of Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Huntington’s Disease (HD), and Amyotrophic Lateral Sclerosis (ALS), affecting both neuronal function and skeletal muscle integrity. Exercise has emerged as a promising, non-pharmacological modulator of ER stress. Chronic, moderate-intensity training generally attenuates ER stress responses, while acute exercise can induce a transient, adaptive stress response. The type and intensity of exercise appear to be critical variables, with modalities like high-intensity interval training showing potential benefits.
However, the existing evidence on how exercise interventions impact ER stress and muscle function in specific neurodegenerative diseases is still developing. While exercise clearly benefits motor function in PD and may reduce brain ER stress in AD, its direct effects on muscle tissue in these conditions require more research. Evidence for exercise in HD is particularly scarce, and its role in ALS remains complex and controversial, necessitating highly individualized and cautious approaches. The intricate crosstalk between ER stress, mitochondrial dysfunction, inflammation, and protein aggregation suggests that the most effective therapeutic strategies will need to target these multiple interconnected pathways.
6.1 Critical context and limitations of the current field
To properly contextualize these findings, it’s important to frame the therapeutic potential of exercise within the current pharmacological landscape. While the ER stress markers discussed are clear pathological contributors, there are currently no FDA-approved drugs that directly target these core Unfolded Protein Response (UPR) pathways for treating neurodegenerative diseases. Research into pharmacological interventions is ongoing, with promising strategies like chemical chaperones (e.g., TUDCA and sodium phenylbutyrate) remaining largely investigational (Ioannou et al., 2025). This therapeutic gap underscores the immense value of non-pharmacological approaches like exercise, which offers a readily available strategy to enhance cellular resilience.
Furthermore, it is critical to address the limitations of extrapolating findings from preclinical rodent models to human conditions. Animal models often fail to capture the complexity of sporadic human diseases, which arise from a mix of genetic and environmental factors. The accelerated disease progression in a short-lived animal does not fully mimic the decades-long development in humans (Alexandra Lopes and Guil-Guerrero, 2025). Significant physiological and metabolic differences mean that the dose, type, and cellular response to an exercise intervention in a mouse cannot be directly translated to a human patient. Therefore, while animal models provide a strong rationale for exercise, their findings must be interpreted with caution.
Finally, future research must carefully consider several potential confounders that influence the relationship between exercise and ER stress. A patient’s diet, for instance, can independently modulate ER stress (Singh et al., 2024; Stults-Kolehmainen and Sinha, 2014). The presence of comorbidities like obesity or type 2 diabetes can create a high basal stress level that may blunt the benefits of exercise (Colberg et al., 2010; Zahalka et al., 2019). Moreover, sex differences and an individual’s lifelong training history are critical factors that can alter the cellular response to an exercise bout. Future clinical trials must be designed to control for these variables to develop truly personalized exercise prescriptions.
6.2 A roadmap for future research and application
6.2.1 Translational considerations and potential biomarkers
A major hurdle in translating preclinical findings is the reliance on invasive muscle biopsies. To facilitate clinical trials, the development of less invasive biomarkers is essential. Potential biomarkers could be tiered based on feasibility and directness:
• Tier 1 (Direct/Invasive): Muscle Biopsies remain the gold standard. Key markers to quantify include the phosphorylation of PERK and eIF2α, mRNA levels of spliced XBP1, and protein levels of adaptive (BiP/GRP78) versus pro-apoptotic (CHOP) markers (Walter et al., 2015; Rozpedek et al., 2016).
• Tier 2 (Less-Invasive/Circulating): Blood-Based Markers offer a more practical alternative. This includes measuring secreted ER chaperones like GRP78/BiP in plasma, though their tissue origin can be ambiguous (Lee, 2005). Other promising candidates include myokines regulated by ER stress, such as Fibroblast Growth Factor 21 (FGF21), and specific circulating microRNAs released from stressed muscle (Lee, 2005; Cicek et al., 2024).
• Tier 3 (Functional/Imaging): Non-invasive Proxies can provide indirect evidence of improved cellular health. For example, 31P-magnetic resonance spectroscopy (31P-MRS) can assess mitochondrial function, while advanced ultrasound techniques can measure muscle quality changes that reflect improvements in cellular composition (Bendahan et al., 2006).
6.2.2 Integrating omics and advanced clinical trial designs
Future research should incorporate omics-based findings. High-throughput technologies like transcriptomics, proteomics, and metabolomics can provide an unbiased, systems-level view of the molecular adaptations to exercise. For instance, RNA-sequencing of muscle biopsies from patients in an exercise trial could reveal entire networks of genes related to the UPR and mitochondrial biogenesis, providing a comprehensive signature of exercise’s benefits.
Furthermore, there is a need to enhance the design of clinical trial evidence. Historically, most exercise trials have focused on functional outcomes. A critical future direction is the design of trials that pair these clinical measures with the systematic collection of biological samples for molecular analysis. Measuring ER stress markers as secondary outcomes in human trials is essential to finally link the proposed mechanism to the clinical benefit.
6.2.3 Proposed experimental designs to address current gaps
To move the field forward, research must adopt more sophisticated experimental designs. Preclinically, studies should shift towards models that better mimic the human condition, such as using voluntary exercise in aged or late-stage disease models. A powerful design would be a longitudinal study combining multi-modal exercise with intermittent muscle biopsies for single-cell transcriptomics to understand how different muscle fiber types adapt over time.
Clinically, the next step is to implement longitudinal, multi-arm intervention trials. A robust design would involve recruiting a well-defined patient cohort (e.g., early-stage PD) and randomizing them into groups: (1) a control group, (2) a moderate-intensity continuous training group, and (3) a high-intensity interval training (HIIT) group. The intervention would last for at least 6 months, with multi-layered outcomes including (a) functional measures (e.g., 6-min walk test), (b) invasive molecular measures (muscle biopsies), and (c) non-invasive biomarkers.
6.2.4 Framework for implementing individualized exercise prescriptions
Moving from principle to practice requires a clear framework for individualizing exercise. A multidisciplinary approach is essential and should include:
1. Comprehensive Baseline Assessment: Each patient must undergo a thorough evaluation by a team including a physician and a physical therapist to assess disease stage, functional capacity, comorbidities, and the patient’s personal goals.
2. Prescription Based on “Start Low, Go Slow”: The initial prescription should be conservative. Intensity can be guided by the Rating of Perceived Exertion (RPE) scale and heart rate monitoring, with the program progressively titrated based on tolerance.
3. Integration of Wearable Technology: Modern wearables can provide real-world data on activity, sleep, and heart rate variability, allowing for remote monitoring and patient self-management.
4. Future Biomarker-Guided Personalization: The ultimate goal of “precision exercise medicine” is to create a feedback loop where a patient’s exercise prescription is adjusted not just based on function, but also on how their molecular biomarkers respond to the training, ensuring the dose is optimized to promote an adaptive cellular response.
Author contributions
ZS: Conceptualization, Data curation, Investigation, Methodology, Software, Supervision, Validation, Writing – original draft, Writing – review & editing. LX: Data curation, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by Research Project of Humanities and Social Sciences, Ministry of Education in 2024 (24YJE890001); Science Research Key Project of Anhui Provincial Department of Education in 2023 (2023AH051526).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Afroze, D., and Kumar, A. (2019). ER stress in skeletal muscle remodeling and myopathies. FEBS J. 286, 379–398. doi: 10.1111/febs.14358
Ajoolabady, A., Lindholm, D., Ren, J., and Pratico, D. (2022). ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments. Cell Death Dis. 13:706. doi: 10.1038/s41419-022-05153-5
Alexandra Lopes, P., and Guil-Guerrero, J. L. (2025). Beyond transgenic mice: emerging models and translational strategies in Alzheimer’s disease. Int. J. Mol. Sci. 26. doi: 10.3390/ijms26125541
Argilés, J. M., Campos, N., Lopez-Pedrosa, J. M., Rueda, R., and Rodriguez-Mañas, L. (2016). Skeletal muscle regulates metabolism via interorgan crosstalk: roles in health and disease. J. Am. Med. Dir. Assoc. 17, 789–796. doi: 10.1016/j.jamda.2016.04.019
Baar, K. (2004). Involvement of PPARγ co-activator-1, nuclear respiratory factors 1 and 2, and PPARα in the adaptive response to endurance exercise. Proc. Nutr. Soc. 63, 269–273. doi: 10.1079/PNS2004334
Baek, J.-H., Mamula, D., Tingstam, B., Pereira, M., He, Y., and Svenningsson, P. (2019). GRP78 level is altered in the brain, but not in plasma or cerebrospinal fluid in Parkinson’s disease patients. Front. Neurosci. 13:697. doi: 10.3389/fnins.2019.00697
Barron, J. C., Hurley, E. P., and Parsons, M. P. (2021). Huntingtin and the synapse. Front. Cell. Neurosci. 15:689332. doi: 10.3389/fncel.2021.689332
Bendahan, D., Mattei, J. P., Guis, S., Kozak-Ribbens, G., and Cozzone, P. J. (2006). Non-invasive investigation of muscle function using 31P magnetic resonance spectroscopy and 1H MR imaging. Rev. Neurol. (Paris) 162, 467–484. doi: 10.1016/S0035-3787(06)75038-X
Berchtold, M. W., Brinkmeier, H., and Muntener, M. (2000). Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiol. Rev. 80, 1215–1265. doi: 10.1152/physrev.2000.80.3.1215
Berg, R. L., and Cassells, J. S. (1992). Falls in older persons: Risk factors and prevention. The second fifty years: Promoting health and preventing disability : National Academies Press (US).
Bernard-Marissal, N., Medard, J.-J., Azzedine, H., and Chrast, R. (2015). Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain 138, 875–890. doi: 10.1093/brain/awv008
Bohnert, K. R., McMillan, J. D., and Kumar, A. (2018). Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. J. Cell. Physiol. 233, 67–78. doi: 10.1002/jcp.25852
Borrione, P., Tranchita, E., Sansone, P., and Parisi, A. (2014). Effects of physical activity in Parkinson’s disease: a new tool for rehabilitation. World J. Methodol. 4, 133–143. doi: 10.5662/wjm.v4.i3.133
Bravo, R., Gutierrez, T., Paredes, F., Gatica, D., Rodriguez, A. E., Pedrozo, Z., et al. (2012). Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics. Int. J. Biochem. Cell Biol. 44, 16–20. doi: 10.1016/j.biocel.2011.10.012
Burtscher, J., Millet, G. P., Place, N., Kayser, B., and Zanou, N. (2021). The muscle-brain axis and neurodegenerative diseases: the key role of mitochondria in exercise-induced neuroprotection. Int. J. Mol. Sci. 22:6479. doi: 10.3390/ijms22126479
Castelli, S., Carinci, E., and Baldelli, S. (2025). Oxidative stress in neurodegenerative disorders: A key driver in impairing skeletal muscle health. Int. J. Mol. Sci. 26:5782. doi: 10.3390/ijms26125782
Chapman, L., Cooper-Knock, J., and Shaw, P. J. (2023). Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence. Brain 146, 1745–1757. doi: 10.1093/brain/awac470
Chen, A., Montes, J., and Mitsumoto, H. (2008). The role of exercise in amyotrophic lateral sclerosis. Phys. Med. Rehabil. Clin. N. Am. 19, 545–557. doi: 10.1016/j.pmr.2008.02.003
Chen, D., Wang, Y., and Chin, E. R. (2015). Activation of the endoplasmic reticulum stress response in skeletal muscle of G93A* SOD1 amyotrophic lateral sclerosis mice. Front. Cell. Neurosci. 9:170. doi: 10.3389/fncel.2015.00170
Chen, D., Zhang, S., Sheng, S., Cai, L., Zheng, J., Zhang, Y., et al. (2023) Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways.
Cicek, C., Telkoparan-Akillilar, P., Sertyel, S., Bilgi, C., and Ozgun, O. D. (2024). Investigation of endoplasmic reticulum stress-regulated chaperones as biomarkers in idiopathic nonobstructive azoospermia. Cell Stress Chaperones 29, 654–665. doi: 10.1016/j.cstres.2024.08.004
Cirone, M. (2021). ER stress, UPR activation and the inflammatory response to viral infection. Viruses 13:798. doi: 10.3390/v13050798
Cisbani, G., and Cicchetti, F. (2012). An in vitro perspective on the molecular mechanisms underlying mutant huntingtin protein toxicity. Cell Death Dis. 3:e382. doi: 10.1038/cddis.2012.121
Colberg, S. R., Sigal, R. J., Fernhall, B., Regensteiner, J. G., Blissmer, B. J., Rubin, R. R., et al. (2010). Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care 33, e147–e167. doi: 10.2337/dc10-9990
Coleman, O. I., and Haller, D. (2019). ER stress and the UPR in shaping intestinal tissue homeostasis and immunity. Front. Immunol. 10:2825. doi: 10.3389/fimmu.2019.02825
D’Angelo, M. G., and Bresolin, N. (2006). Cognitive impairment in neuromuscular disorders. Muscle Nerve 34, 16–33. doi: 10.1002/mus.20535
de Almeida, J. L., Silvestre, R., Pinto, A., and De Carvalho, M. (2012). Exercise and amyotrophic lateral sclerosis. Neurol. Sci. 33, 9–15.
de Lemos, E. T., Oliveira, J., Pinheiro, J. P., and Reis, F. (2012). Regular physical exercise as a strategy to improve antioxidant and anti-inflammatory status: benefits in type 2 diabetes mellitus. Oxidative Med. Cell. Longev. 2012:741545.
de Lima, E. P., Tanaka, M., Lamas, C. B., Quesada, K., Detregiachi, C. R. P., Araújo, A. C., et al. (2024). Vascular impairment, muscle atrophy, and cognitive decline: critical age-related conditions. Biomedicine 12:2096. doi: 10.3390/biomedicines12092096
de Mena, L., Lopez-Scarim, J., and Rincon-Limas, D. E. (2021). TDP-43 and ER stress in neurodegeneration: friends or foes? Front. Mol. Neurosci. 14:772226. doi: 10.3389/fnmol.2021.772226
de Sousa Fernandes, M. S., Badicu, G., Santos, G. C. J., Filgueira, T., Henrique, R. S., de Souza, R. F., et al. (2023). Physical exercise decreases endoplasmic reticulum stress in central and peripheral tissues of rodents: a systematic review. Eur. J. Investig. Health Psychol. Educ. 13, 1082–1096. doi: 10.3390/ejihpe13060082
Deldicque, L. (2013). Endoplasmic reticulum stress in human skeletal muscle: any contribution to sarcopenia? Front. Physiol. 4:236. doi: 10.3389/fphys.2013.00236
Delmotte, P., and Sieck, G. C. (2015). Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca2+ regulation in airway smooth muscle (ASM). Can. J. Physiol. Pharmacol. 93, 97–110. doi: 10.1139/cjpp-2014-0361
Dishman, R. K., Berthoud, H. R., Booth, F. W., Cotman, C. W., Edgerton, V. R., Fleshner, M. R., et al. (2006). Neurobiology of exercise. Obesity 14, 345–356. doi: 10.1038/oby.2006.46
Dobrowolny, G., Barbiera, A., Sica, G., and Scicchitano, B. M. (2021). Age-related alterations at neuromuscular junction: role of oxidative stress and epigenetic modifications. Cells 10. doi: 10.3390/cells10061307
Duranti, E., and Villa, C. (2023). Muscle involvement in amyotrophic lateral sclerosis: understanding the pathogenesis and advancing therapeutics. Biomolecules. 13:1582. doi: 10.3390/biom13111582
Duranti, E., and Villa, C. (2024). From brain to muscle: the role of muscle tissue in neurodegenerative disorders. Biology 13:719. doi: 10.3390/biology13090719
Egan, B., and Sharples, A. P. (2023). Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training. Physiol. Rev. 103, 2057–2170. doi: 10.1152/physrev.00054.2021
Ekundayo, B. E., Obafemi, T. O., Adewale, O. B., Obafemi, B. A., Oyinloye, B. E., and Ekundayo, S. K. (2024). Oxidative stress, endoplasmic reticulum stress and apoptosis in the pathology of Alzheimer’s disease. Cell Biochem. Biophys. 82, 457–477. doi: 10.1007/s12013-024-01248-2
El Assar, M., Álvarez-Bustos, A., Sosa, P., Angulo, J., and Rodríguez-Mañas, L. (2022). Effect of physical activity/exercise on oxidative stress and inflammation in muscle and vascular aging. Int. J. Mol. Sci. 23:8713. doi: 10.3390/ijms23158713
Endres, K., and Reinhardt, S. (2013). ER-stress in Alzheimer’s disease: turning the scale? Am. J. Neurodegener. Dis. 2:247.
Ernst, M., Folkerts, A. K., Gollan, R., Lieker, E., Caro-Valenzuela, J., Adams, A., et al. (2023). Physical exercise for people with Parkinson’s disease: a systematic review and network meta-analysis. Cochrane Database Syst. Rev. 1:Cd013856. doi: 10.1002/14651858.CD013856.pub2
Estébanez, B., De Paz, J. A., Cuevas, M. J., and González-Gallego, J. (2018). Endoplasmic reticulum unfolded protein response, aging and exercise: an update. Front. Physiol. 9:1744. doi: 10.3389/fphys.2018.01744
Falvo, M. J., Schilling, B. K., and Earhart, G. M. (2008). Parkinson’s disease and resistive exercise: rationale, review, and recommendations. Mov. Disord. 23, 1–11. doi: 10.1002/mds.21690
Fang, Z., Gao, W., Jiang, Q., Loor, J. J., Zhao, C., Du, X., et al. (2022). Targeting IRE1α and PERK in the endoplasmic reticulum stress pathway attenuates fatty acid-induced insulin resistance in bovine hepatocytes. J. Dairy Sci. 105, 6895–6908. doi: 10.3168/jds.2021-21754
Feng, H., Kang, C., Dickman, J. R., Koenig, R., Awoyinka, I., Zhang, Y., et al. (2013). Training-induced mitochondrial adaptation: role of peroxisome proliferator-activated receptor γ coactivator-1α, nuclear factor-κB and β-blockade. Exp. Physiol. 98, 784–795. doi: 10.1113/expphysiol.2012.069286
Flynn, M. G., McFarlin, B. K., and Markofski, M. M. (2007). The anti-inflammatory actions of exercise training. Am. J. Lifestyle Med. 1, 220–235. doi: 10.1177/1559827607300283
Galbiati, M., Crippa, V., Rusmini, P., Cristofani, R., Cicardi, M. E., Giorgetti, E., et al. (2014). ALS-related misfolded protein management in motor neurons and muscle cells. Neurochem. Int. 79, 70–78. doi: 10.1016/j.neuint.2014.10.007
Gallot, Y. S., and Bohnert, K. R. (2021). Confounding roles of ER stress and the unfolded protein response in skeletal muscle atrophy. Int. J. Mol. Sci. 22:2567. doi: 10.3390/ijms22052567
Gao, B., Wang, L., Gong, J., Zhu, Z., Liu, Q., Yuan, H., et al. (2025). The interplay between physical exercise and autophagy signaling in brain health, neurodegenerative diseases and aging. Front. Aging Neurosci. 17.
Gil, J. M., and Rego, A. C. (2008). Mechanisms of neurodegeneration in Huntington’s disease. Eur. J. Neurosci. 27, 2803–2820. doi: 10.1111/j.1460-9568.2008.06310.x
Goh, A. M., Wibawa, P., Loi, S. M., Walterfang, M., Velakoulis, D., and Looi, J. C. (2018). Huntington’s disease: neuropsychiatric manifestations of Huntington’s disease. Australas. Psychiatry 26, 366–375. doi: 10.1177/1039856218791036
Gordon, B. S., Kelleher, A. R., and Kimball, S. R. (2013). Regulation of muscle protein synthesis and the effects of catabolic states. Int. J. Biochem. Cell Biol. 45, 2147–2157. doi: 10.1016/j.biocel.2013.05.039
Gregersen, N., and Bross, P. (2010). “Protein misfolding and cellular stress: an overview” in Protein Misfolding and cellular stress in disease and aging: concepts and protocols, 3–23.
Hu, M., and Robertson, N. P. (2020). Physical activity as a risk factor for amyotrophic lateral sclerosis-findings from three large European cohorts. J. Neurol. 267, 2173–2175.
Hassab, L. Y., Abbas, S. S., Mohammed, R. A., and Abdallah, D. M. (2023). Dimethyl fumarate abrogates striatal endoplasmic reticulum stress in experimentally induced late-stage Huntington’s disease: focus on the IRE1α/JNK and PERK/CHOP trajectories. Front. Pharmacol. 14:1133863. doi: 10.3389/fphar.2023.1133863
Hetz, C., and Papa, F. R. (2018). The unfolded protein response and cell fate control. Mol. Cell 69, 169–181. doi: 10.1016/j.molcel.2017.06.017
Hong, J., Hong, S.-G., Lee, J., Park, J.-Y., Eriksen, J. L., Rooney, B. V., et al. (2020). Exercise training ameliorates cerebrovascular dysfunction in a murine model of Alzheimer’s disease: role of the P2Y2 receptor and endoplasmic reticulum stress. Am. J. Phys. Heart Circ. Phys. 318, H1559–H1569. doi: 10.1152/ajpheart.00129.2020
Hotamisligil, G. S. (2010). Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900–917. doi: 10.1016/j.cell.2010.02.034
Hu, C., Yang, J., Qi, Z., Wu, H., Wang, B., Zou, F., et al. (2022). Heat shock proteins: biological functions, pathological roles, and therapeutic opportunities. MedComm 3:e161.
Ioannou, P., Odiatis, C., Hadjisavva, R., Antoniadou, K., Pieri, M., Malatras, A., et al. (2025). Chemical chaperone 4-phenylbutyrate treatment alleviates the kidney phenotype in a mouse model of Alport syndrome with a pathogenic variant in Col4a3. Kidney Int. doi: 10.1016/j.kint.2025.05.016
Ito, N., Ruegg, U. T., and Takeda, S. (2018). ATP-induced increase in intracellular calcium levels and subsequent activation of mTOR as regulators of skeletal muscle hypertrophy. Int. J. Mol. Sci. 19:2804. doi: 10.3390/ijms19092804
Jeon, Y.-M., Kwon, Y., Lee, S., and Kim, H.-J. (2023). Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis. Front. Aging Neurosci. 15:1047897. doi: 10.3389/fnagi.2023.1047897
Jesse, C. M., Bushuven, E., Tripathi, P., Chandrasekar, A., Simon, C. M., Drepper, C., et al. (2017). ALS-associated endoplasmic reticulum proteins in denervated skeletal muscle: implications for motor neuron disease pathology. Brain Pathol. 27, 781–794. doi: 10.1111/bpa.12453
Jodeiri Farshbaf, M., and Ghaedi, K. (2017). Huntington’s disease and mitochondria. Neurotox. Res. 32, 518–529. doi: 10.1007/s12640-017-9766-1
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., et al. (2023). Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch. Toxicol. 97, 2499–2574. doi: 10.1007/s00204-023-03562-9
Joshi, D. C., Chavan, M. B., Gurow, K., Gupta, M., Dhaliwal, J. S., and Ming, L. C. (2025). The role of mitochondrial dysfunction in Huntington’s disease: implications for therapeutic targeting. Biomed. Pharmacother. 183:117827. doi: 10.1016/j.biopha.2025.117827
Jung, S., and Kim, K. (2014). Exercise-induced PGC-1α transcriptional factors in skeletal muscle. Integr. Med. Res. 3, 155–160. doi: 10.1016/j.imr.2014.09.004
Kadowaki, H., and Nishitoh, H. (2013). Signaling pathways from the endoplasmic reticulum and their roles in disease. Genes (Basel) 4, 306–333. doi: 10.3390/genes4030306
Kameyama, T., and Etlinger, J. D. (1979). Calcium-dependent regulation of protein synthesis and degradation in muscle. Nature 279, 344–346. doi: 10.1038/279344a0
Kano, Y., Sonobe, T., Inagaki, T., Sudo, M., and Poole, D. C. (2012). Mechanisms of exercise-induced muscle damage and fatigue: intracellular calcium accumulation. J. Phys. Fit. Sports Med. 1, 505–512. doi: 10.7600/jpfsm.1.505
Kaufman, R. J., Back, S. H., Song, B., Han, J., and Hassler, J. (2010). The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β-cells. Diabetes Obes. Metab. 12, 99–107.
Kelly, N. A., Ford, M. P., Standaert, D. G., Watts, R. L., Bickel, C. S., Moellering, D. R., et al. (2014). Novel, high-intensity exercise prescription improves muscle mass, mitochondrial function, and physical capacity in individuals with Parkinson’s disease. J. Appl. Physiol. 116, 582–592. doi: 10.1152/japplphysiol.01277.2013
Khadir, A., Kavalakatt, S., Abubaker, J., Cherian, P., Madhu, D., Al-Khairi, I., et al. (2016). Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone. Metabolism 65, 1409–1420. doi: 10.1016/j.metabol.2016.06.004
Kim, K., Ahn, N., and Jung, S. (2018). Comparison of endoplasmic reticulum stress and mitochondrial biogenesis responses after 12 weeks of treadmill running and ladder climbing exercises in the cardiac muscle of middle-aged obese rats. Braz. J. Med. Biol. Res. 51:e7508. doi: 10.1590/1414-431x20187508
Kim, K., Kim, Y.-H., Lee, S.-H., Jeon, M.-J., Park, S.-Y., and Doh, K.-O. (2014). Effect of exercise intensity on unfolded protein response in skeletal muscle of rat. Korean J. Physiol. Pharmacol. 18, 211–216. doi: 10.4196/kjpp.2014.18.3.211
Kim, Y., Park, M., Boghossian, S., and York, D. A. (2010). Three weeks voluntary running wheel exercise increases endoplasmic reticulum stress in the brain of mice. Brain Res. 1317, 13–23. doi: 10.1016/j.brainres.2009.12.062
Kong, X., Liu, T., and Wei, J. (2025). Parkinson’s disease: the neurodegenerative enigma under the “undercurrent” of endoplasmic reticulum stress. Int. J. Mol. Sci. 26:3367. doi: 10.3390/ijms26073367
Korkmaz, K., Düzova, H., Taşlidere, A. Ç., Koç, A., Karaca, Z., and Durmuş, K. (2023). Effect of high-intensity exercise on endoplasmic reticulum stress and proinflammatory cytokine levels. Sci. Sports. 38:428.e1-e10.
Koulmann, N., and Bigard, A.-X. (2006). Interaction between signalling pathways involved in skeletal muscle responses to endurance exercise. Pflügers Arch. 452, 125–139. doi: 10.1007/s00424-005-0030-9
Kowalczyk, P., Sulejczak, D., Kleczkowska, P., Bukowska-Ośko, I., Kucia, M., Popiel, M., et al. (2021). Mitochondrial oxidative stress-A causative factor and therapeutic target in many diseases. Int. J. Mol. Sci. 22. doi: 10.3390/ijms222413384
Kristensen, C. M., Jessen, H., Ringholm, S., and Pilegaard, H. (2018). Muscle PGC-1α in exercise and fasting-induced regulation of hepatic UPR in mice. Acta Physiol. 224:e13158. doi: 10.1111/apha.13158
Kumar, A., and Ratan, R. R. (2016). Oxidative stress and Huntington’s disease: the good, the bad, and the ugly. J Huntingtons Dis. 5, 217–237. doi: 10.3233/JHD-160205
Kyriazis, I. D., Vassi, E., Alvanou, M., Angelakis, C., Skaperda, Z., Tekos, F., et al. (2022). The impact of diet upon mitochondrial physiology (review). Int. J. Mol. Med. 50. doi: 10.3892/ijmm.2022.5191
Lange-Asschenfeldt, C., and Kojda, G. (2008). Alzheimer’s disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons. Exp. Gerontol. 43, 499–504. doi: 10.1016/j.exger.2008.04.002
Lee, A. S. (2005). The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods 35, 373–381. doi: 10.1016/j.ymeth.2004.10.010
Lee, B., Shin, M., Park, Y., Won, S. Y., and Cho, K. S. (2021). Physical exercise-induced Myokines in neurodegenerative diseases. Int. J. Mol. Sci. 22. doi: 10.3390/ijms22115795
Lee, S. S., Yoo, J. H., and So, Y. S. (2015). Effect of the low-versus high-intensity exercise training on endoplasmic reticulum stress and GLP-1 in adolescents with type 2 diabetes mellitus. J. Phys. Ther. Sci. 27, 3063–3068. doi: 10.1589/jpts.27.3063
Li, Y. (2023). Endoplasmic reticulum dysfunction and Parkinson’s disease. Highl. Sci. Eng. Technol. 36, 792–797. doi: 10.54097/hset.v36i.5798
Li, Y. Y., Qin, Z. H., and Sheng, R. (2024). The multiple roles of autophagy in neural function and diseases. Neurosci. Bull. 40, 363–382. doi: 10.1007/s12264-023-01120-y
Li, F.-H., Sun, L., Wu, D.-S., Gao, H.-E., and Min, Z. (2019). Proteomics-based identification of different training adaptations of aged skeletal muscle following long-term high-intensity interval and moderate-intensity continuous training in aged rats. Aging (Albany NY) 11, 4159–4182. doi: 10.18632/aging.102044
Li, J.-Q., Yu, J.-T., Jiang, T., and Tan, L. (2015). Endoplasmic reticulum dysfunction in Alzheimer’s disease. Mol. Neurobiol. 51, 383–395. doi: 10.1007/s12035-014-8695-8
Lin, S., Wu, J., Lian, G., Wu, W., Chen, W., Chen, A., et al. (2025). Protective effects of Salubrinal against H2O2-induced muscle wasting via eIF2α/ATF4 signaling pathway. Front. Pharmacol. 16:2025.
Lira, V. A., Benton, C. R., Yan, Z., and Bonen, A. (2010). PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 299, E145–E161. doi: 10.1152/ajpendo.00755.2009
Liu, W., He, W., and Li, H. (2013). Exhaustive training increases uncoupling protein 2 expression and decreases Bcl-2/Bax ratio in rat skeletal muscle. Oxidative Med. Cell. Longev. 2013:780719. doi: 10.1155/2013/780719
Loeffler, J. P., Picchiarelli, G., Dupuis, L., and Gonzalez De Aguilar, J. L. (2016). The role of skeletal muscle in amyotrophic lateral sclerosis. Brain Pathol. 26, 227–236. doi: 10.1111/bpa.12350
Lontay, B., Kiss, A., Virág, L., and Tar, K. (2020). How do post-translational modifications influence the pathomechanistic landscape of Huntington’s disease? A comprehensive review. Int. J. Mol. Sci. 21:4282. doi: 10.3390/ijms21124282
Maity, S., Komal, P., Kumar, V., Saxena, A., Tungekar, A., and Chandrasekar, V. (2022). Impact of ER stress and ER-mitochondrial crosstalk in Huntington’s disease. Int. J. Mol. Sci. 23:780. doi: 10.3390/ijms23020780
Manzanares, G., Brito-da-Silva, G., and Gandra, P. G. (2018). Voluntary wheel running: patterns and physiological effects in mice. Braz. J. Med. Biol. Res. 52:e7830. doi: 10.1590/1414-431x20187830
Marafon, B. B. Role of TLR4 in endoplasmic reticulum stress induced by physical exercise in skeletal muscle: Universidade de São Paulo; (2022)
Marafon, B. B., Pinto, A. P., Ropelle, E. R., de Moura, L. P., Cintra, D. E., Pauli, J. R., et al. (2022). Muscle endoplasmic reticulum stress in exercise. Acta Physiol. 235:e13799. doi: 10.1111/apha.13799
Marques-Aleixo, I., Beleza, J., Sampaio, A., Stevanović, J., Coxito, P., Gonçalves, I., et al. (2021). Preventive and therapeutic potential of physical exercise in neurodegenerative diseases. Antioxid. Redox Signal. 34, 674–693. doi: 10.1089/ars.2020.8075
Medinas, D. B., Hazari, Y., and Hetz, C. (2021). “Disruption of endoplasmic reticulum proteostasis in age-related nervous system disorders” in Cellular Biology of the Endoplasmic Reticulum (Springer), 239.
Mehanna, R., and Jankovic, J. (2024). Systemic symptoms in Huntington’s disease: A comprehensive review. Mov Disord Clin Pract 11, 453–464. doi: 10.1002/mdc3.14029
Memme, J. M., Erlich, A. T., Phukan, G., and Hood, D. A. (2021). Exercise and mitochondrial health. J. Physiol. 599, 803–817. doi: 10.1113/JP278853
Memme, J. M., and Hood, D. A. (2020). Molecular basis for the therapeutic effects of exercise on mitochondrial defects. Front. Physiol. 11:615038. doi: 10.3389/fphys.2020.615038
Mercado, G., Castillo, V., Soto, P., and Sidhu, A. (2016). ER stress and Parkinson’s disease: pathological inputs that converge into the secretory pathway. Brain Res. 1648, 626–632. doi: 10.1016/j.brainres.2016.04.042
Misrani, A., Tabassum, S., and Yang, L. (2021). Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease. Front. Aging Neurosci. 13:617588. doi: 10.3389/fnagi.2021.617588
Nagaraju, K., Casciola-Rosen, L., Lundberg, I., Rawat, R., Cutting, S., Thapliyal, R., et al. (2005). Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum. 52, 1824–1835. doi: 10.1002/art.21103
Nishikawa, S.-i., Brodsky, J. L., and Nakatsukasa, K. (2005). Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). J. Biochem. 137:551. doi: 10.1093/jb/mvi068
Ogborn, D. I. (2013) Characterizing the acute mitochondrial response to resistance exercise in aging
Palakurthi, B., and Burugupally, S. P. (2019). Postural instability in Parkinson’s disease: a review. Brain Sci. 9:239. doi: 10.3390/brainsci9090239
Paschen, W., and Doutheil, J. (1999). Disturbances of the functioning of endoplasmic reticulum: a key mechanism underlying neuronal cell injury? J. Cereb. Blood Flow Metab. 19, 1–18. doi: 10.1097/00004647-199901000-00001
Pereira, B. C., Da Rocha, A. L., Pinto, A. P., Pauli, J. R., De Souza, C. T., Cintra, D. E., et al. (2016). Excessive eccentric exercise-induced overtraining model leads to endoplasmic reticulum stress in mice skeletal muscles. Life Sci. 145, 144–151. doi: 10.1016/j.lfs.2015.12.037
Petriz, B. A., Gomes, C. P., Almeida, J. A., de Oliveira, G. P. Jr., Ribeiro, F. M., Pereira, R. W., et al. (2017). The effects of acute and chronic exercise on skeletal muscle proteome. J. Cell. Physiol. 232, 257–269.
Rai, M., and Demontis, F. (2022). Muscle-to-brain signaling via myokines and myometabolites. Brain Plast. 8, 43–63. doi: 10.3233/BPL-210133
Ribarič, S. (2022). Physical exercise, a potential non-pharmacological intervention for attenuating neuroinflammation and cognitive decline in Alzheimer’s disease patients. Int. J. Mol. Sci. 23:3245. doi: 10.3390/ijms23063245
Ropelle, E. R., Flores, M. B., Cintra, D. E., Rocha, G. Z., Pauli, J. R., Morari, J., et al. (2010). IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKβ and ER stress inhibition. PLoS Biol. 8:e1000465. doi: 10.1371/journal.pbio.1000465
Rotariu, D., Babes, E. E., Tit, D. M., Moisi, M., Bustea, C., Stoicescu, M., et al. (2022). Oxidative stress–complex pathological issues concerning the hallmark of cardiovascular and metabolic disorders. Biomed. Pharmacother. 152:113238. doi: 10.1016/j.biopha.2022.113238
Rozpedek, W., Pytel, D., Mucha, B., Leszczynska, H., Diehl, J. A., and Majsterek, I. (2016). The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med. 16, 533–544. doi: 10.2174/1566524016666160523143937
Saaoud, F., Lu, Y., Xu, K., Shao, Y., Praticò, D., Vazquez-Padron, R. I., et al. (2024). Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers – targeting PERK as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer. Pharmacol. Ther. 255:108604. doi: 10.1016/j.pharmthera.2024.108604
Salminen, A., Kaarniranta, K., and Kauppinen, A. (2020). ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease. J. Mol. Med. (Berl) 98, 633–650. doi: 10.1007/s00109-020-01904-z
Sano, R., and Reed, J. C. (2013). ER stress-induced cell death mechanisms. Biochim. Biophys. Acta 1833, 3460–3470. doi: 10.1016/j.bbamcr.2013.06.028
Santiago, J. A., and Potashkin, J. A. (2023). Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases. Front. Aging Neurosci. 15:1185671. doi: 10.3389/fnagi.2023.1185671
Scaricamazza, S., Nesci, V., Salvatori, I., Fenili, G., Rosina, M., Gloriani, M., et al. (2024). Endurance exercise has a negative impact on the onset of SOD1-G93A ALS in female mice and affects the entire skeletal muscle-motor neuron axis. Front. Pharmacol. 15. doi: 10.3389/fphar.2024.1360099
Schootemeijer, S., van der Kolk, N. M., Bloem, B. R., and de Vries, N. M. (2020). Current perspectives on aerobic exercise in people with Parkinson’s disease. Neurotherapeutics 17, 1418–1433. doi: 10.1007/s13311-020-00904-8
Schröder, M., and Kaufman, R. J. (2005). ER stress and the unfolded protein response. Mutat Res 569, 29–63. doi: 10.1016/j.mrfmmm.2004.06.056
Senft, D., and Ronai, Z. A. (2015). UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem. Sci. 40, 141–148. doi: 10.1016/j.tibs.2015.01.002
Sheikh, A. M., and Vissing, J. (2019). Exercise therapy for muscle and lower motor neuron diseases. Acta Myol. 38, 215–232. doi: 10.1155/2009/741087
Siciliano, G., Chico, L., Lo Gerfo, A., Simoncini, C., Schirinzi, E., and Ricci, G. (2020). Exercise-related oxidative stress as mechanism to fight physical dysfunction in neuromuscular disorders. Front. Physiol. 11:451. doi: 10.3389/fphys.2020.00451
Silva, M. G., Nunes, P., Oliveira, P., Ferreira, R., Fardilha, M., Moreira-Gonçalves, D., et al. (2022). Long-term aerobic training improves mitochondrial and antioxidant function in the liver of Wistar rats preventing hepatic age-related function decline. Biology 11:1750. doi: 10.3390/biology11121750
Simha, P. K., Mukherjee, C., Bhatia, K., Gupta, V. K., Sapariya, N. M., Nagar, P., et al. (2023). Sida cordifolia, a medicinal plant, is efficacious in models of Huntington’s disease by reducing ER stress. bioRxiv. :2023.11.01.565080.
Simha, P. K., Mukherjee, C., Gupta, V. K., Bhatia, K., Nagar, P., Za, A. N., et al. (2025). Sida cordifolia is efficacious in models of Huntington’s disease by reducing ER stress. Front. Mol. Biosci. 12:1567932. doi: 10.3389/fmolb.2025.1567932
Simioni, C., Zauli, G., Martelli, A. M., Vitale, M., Sacchetti, G., Gonelli, A., et al. (2018). Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging. Oncotarget 9, 17181–17198. doi: 10.18632/oncotarget.24729
Singh, S., Kriti, M., A, K. S., Sarma, D. K., Verma, V., Nagpal, R., et al. (2024). Deciphering the complex interplay of risk factors in type 2 diabetes mellitus: a comprehensive review. Metab. Open. 22:100287.
Siwecka, N., Rozpędek, W., Pytel, D., Wawrzynkiewicz, A., Dziki, A., Dziki, Ł., et al. (2019). Dual role of endoplasmic reticulum stress-mediated unfolded protein response signaling pathway in carcinogenesis. Int. J. Mol. Sci. 20:4354. doi: 10.3390/ijms20184354
Stults-Kolehmainen, M. A., and Sinha, R. (2014). The effects of stress on physical activity and exercise. Sports Med. 44, 81–121. doi: 10.1007/s40279-013-0090-5
Tabas, I., and Ron, D. (2011). Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol. 13, 184–190. doi: 10.1038/ncb0311-184
Tan, Z.-X., Dong, F., Wu, L.-Y., Feng, Y.-S., and Zhang, F. (2021). The beneficial role of exercise on treating Alzheimer’s disease by inhibiting β-amyloid peptide. Mol. Neurobiol. 58, 5890–5906. doi: 10.1007/s12035-021-02514-7
Tiryaki, E., and Horak, H. A. (2014). ALS and other motor neuron diseases. Continuum 20, 1185–1207. doi: 10.1212/01.CON.0000455886.14298.a4
Tsitkanou, S., Della Gatta, P., Foletta, V., and Russell, A. (2019). The role of exercise as a non-pharmacological therapeutic approach for amyotrophic lateral sclerosis: beneficial or detrimental? Front. Neurol. 10:783. doi: 10.3389/fneur.2019.00783
Tung, C. W., Chan, S. C., Cheng, P. H., Chen, Y. C., Wu, P. M., Lin, W. C., et al. (2025). Exploring Cordycepin as a neuroprotective agent in Huntington’s disease: in vitro and in vivo insights. Pharmacol. Res. Perspect. 13:e70091. doi: 10.1002/prp2.70091
Uddin, M. S., Tewari, D., Sharma, G., Kabir, M. T., Barreto, G. E., Bin-Jumah, M. N., et al. (2020). Molecular mechanisms of ER stress and UPR in the pathogenesis of Alzheimer’s disease. Mol. Neurobiol. 57, 2902–2919. doi: 10.1007/s12035-020-01929-y
Vargas-Mendoza, N., Morales-González, Á., Madrigal-Santillán, E. O., Madrigal-Bujaidar, E., Álvarez-González, I., García-Melo, L. F., et al. (2019). Antioxidant and adaptative response mediated by Nrf2 during physical exercise. Antioxidants. 8:196. doi: 10.3390/antiox8060196
Vidal, R., Caballero, B., Couve, A., and Hetz, C. (2011). Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington’s disease. Curr. Mol. Med. 11, 1–12. doi: 10.2174/156652411794474419
Volgyi, K., Juhász, G., Kovács, Z., and Penke, B. (2015). Dysfunction of endoplasmic reticulum (ER) and mitochondria (MT) in Alzheimer’s disease: the role of the ER-MT cross-talk. Curr. Alzheimer Res. 12, 655–672. doi: 10.2174/1567205012666150710095035
Walter, F., Schmid, J., Düssmann, H., Concannon, C. G., and Prehn, J. H. (2015). Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival. Cell Death Differ. 22, 1502–1516. doi: 10.1038/cdd.2014.241
Wang, R., and Holsinger, R. M. D. (2018). Exercise-induced brain-derived neurotrophic factor expression: therapeutic implications for Alzheimer’s dementia. Ageing Res. Rev. 48, 109–121. doi: 10.1016/j.arr.2018.10.002
Wang, L., Mascher, H., Psilander, N., Blomstrand, E., and Sahlin, K. (2011). Resistance exercise enhances the molecular signaling of mitochondrial biogenesis induced by endurance exercise in human skeletal muscle. J. Appl. Physiol. 111, 1335–1344. doi: 10.1152/japplphysiol.00086.2011
Wang, D., Qu, S., Zhang, Z., Tan, L., Chen, X., Zhong, H.-J., et al. (2023). Strategies targeting endoplasmic reticulum stress to improve Parkinson’s disease. Front. Pharmacol. 14:1288894. doi: 10.3389/fphar.2023.1288894
Wang, M., Zhang, H., Liang, J., Huang, J., and Chen, N. (2023). Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease. J. Neuroinflammation 20:76. doi: 10.1186/s12974-023-02753-6
Wankhede, N. L., Kale, M. B., Upaganlawar, A. B., Taksande, B. G., Umekar, M. J., Behl, T., et al. (2022). Involvement of molecular chaperone in protein-misfolding brain diseases. Biomed. Pharmacother. 147:112647. doi: 10.1016/j.biopha.2022.112647
Wijesekera, L. C., and Leigh, N. P. (2009). Amyotrophic lateral sclerosis. Orphanet J. Rare Dis. 4, 1–22.
Wu, J., Ruas, J. L., Estall, J. L., Rasbach, K. A., Choi, J. H., Ye, L., et al. (2011). The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex. Cell Metab. 13, 160–169. doi: 10.1016/j.cmet.2011.01.003
Xu, L., Li, M., Wei, A., Yang, M., Li, C., Liu, R., et al. (2022). Treadmill exercise promotes E3 ubiquitin ligase to remove amyloid β and P-tau and improve cognitive ability in APP/PS1 transgenic mice. J. Neuroinflammation 19:243. doi: 10.1186/s12974-022-02607-7
Yadav, A., and Dabur, R. (2024). Skeletal muscle atrophy after sciatic nerve damage: mechanistic insights. Eur. J. Pharmacol. 970:176506. doi: 10.1016/j.ejphar.2024.176506
Yang, Y., Liu, L., Naik, I., Braunstein, Z., Zhong, J., and Ren, B. (2017). Transcription factor C/EBP homologous protein in health and diseases. Front. Immunol. 8:1612. doi: 10.3389/fimmu.2017.01612
Zahalka, S. J., Abushamat, L. A., Scalzo, R. L., and Reusch, J. E. The role of exercise in diabetes (2019)
Zhang, H.-Y., Wang, Z.-G., Lu, X.-H., Kong, X.-X., Wu, F.-Z., Lin, L., et al. (2015). Endoplasmic reticulum stress: relevance and therapeutics in central nervous system diseases. Mol. Neurobiol. 51, 1343–1352. doi: 10.1007/s12035-014-8813-7
Zhang, S.-S., Zhou, S., Crowley-McHattan, Z. J., Wang, R.-Y., and Li, J.-P. (2021). A review of the role of endo/sarcoplasmic reticulum-mitochondria Ca2+ transport in diseases and skeletal muscle function. Int. J. Environ. Res. Public Health 18:3874. doi: 10.3390/ijerph18083874
Keywords: exercise, ER stress, muscle function, neurodegenerative diseases, unfolded protein response
Citation: Su Z and Xiang L (2025) Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline. Front. Mol. Neurosci. 18:1639114. doi: 10.3389/fnmol.2025.1639114
Edited by:
Ulises Gomez-Pinedo, Health Research Institute of Hospital Clínico San Carlos, SpainReviewed by:
Edwin Estefan Reza, Monterrey Institute of Technology and Higher Education (ITESM), MexicoChulhwan Kwak, Stanford University, United States
Mercedes Azucena Hernandez Sapiens, Escuela de Ingenieria y Ciencias, Mexico
Copyright © 2025 Su and Xiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhanguo Su, c3V6aGFuZ3VvQDEyNi5jb20=
†Present address: Zhanguo Su, International College, Krirk University, Bangkok, Thailand