XiangSheng Pang
Peng Zhang
XiaoPing Chen
WenMing Liu1*- 1Department of Physical Education, College of Education, Zhejiang University, Hangzhou, Zhejiang, China
- 2National Key Laboratory of Human Factors Engineering, China Astronaut Research and Training Center, Beijing, China
- 3State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
Skeletal muscles underpin myriad human activities, maintaining an intricate balance between protein synthesis and degradation crucial to muscle mass preservation. Historically, disruptions in this balance—where degradation overshadows synthesis—have marked the onset of muscle atrophy, a condition diminishing life quality and, in grave instances, imperiling life itself. While multiple protein degradation pathways exist—including the autophagy-lysosome, calcium-dependent calpain, and cysteine aspartate protease systems—the ubiquitin-proteasome pathway emerges as an especially cardinal avenue for intracellular protein degradation, wielding pronounced influence over the muscle atrophy trajectory. This paper ventures a panoramic view of predominant muscle atrophy types, accentuating the ubiquitin-proteasome pathway’s role therein. Furthermore, by drawing from recent scholarly advancements, we draw associations between the ubiquitin-proteasome pathway and specific pathological conditions linked to muscle atrophy. Our exploration seeks to shed light on the ubiquitin-proteasome pathway’s significance in skeletal muscle dynamics, aiming to pave the way for innovative therapeutic strategies against muscle atrophy and affiliated muscle disorders.
1 Introduction
Skeletal muscles, constituting over 40% of body weight in healthy adults, stand as the body’s most prolific tissue. Beyond facilitating movement, these muscles function as pivotal protein stores, orchestrating metabolic processes and ensuring glucose equilibrium. Intrinsically designed to swiftly adjust to both external and internal shifts, skeletal muscle’s adaptability becomes fundamental to tissue vitality and overall survival. Central to this functionality is the preservation of muscle mass, critically underpinned by the equilibrium between protein synthesis and degradation. Historically, factors like age, physical activity, and prevailing diseases have swayed protein dynamics. When this balance falters, with protein degradation gaining an upper hand, muscle atrophy, characterized by amplified protein degradation and subdued synthesis, ensues. The ubiquitin-proteasome pathway, a principal conduit for intracellular protein degradation, emerges as a common player in diverse skeletal muscle atrophy types. This article embarks on an exploration of the diverse manifestations of skeletal muscle atrophy. Grounded in this overview, we endeavor to decode and forecast the research trajectories surrounding the ubiquitin-proteasome pathway’s role in muscle atrophy processes, aiming to underpin future interventions and treatments in the realm of muscle disorders.
2 Protein synthesis and proteolysis in skeletal muscle atrophy
Skeletal muscle atrophy is characterized by a disrupted balance between protein synthesis and degradation, typically manifested by suppressed protein synthesis and/or enhanced protein degradation levels [1, 2]. Factors such as exercise and diseases commonly influence protein synthesis and degradation. Resistance training or anabolic hormonal stimuli can enhance protein synthesis, resulting in an increase in skeletal muscle cell protein synthesis, leading to an increase in muscle fiber size, a process known as skeletal muscle hypertrophy [3]. Under catabolic conditions, protein degradation surpasses synthesis, leading to muscle weakness and atrophy. Conditions such as disuse, sarcopenia, cancer-associated cachexia, malnutrition or starvation, and various other pathological states present with skeletal muscle atrophy [4].
Insulin-like growth factor-1 (IGF-1) is a pivotal growth factor in regulating the anabolic and catabolic pathways in skeletal muscles, with the phosphoinositide 3-kinase (PI3K)-AKT pathway considered the primary signaling protein cascade controlling muscle protein content [5]. Within skeletal muscle, the IGF-1-mediated PI3K/AKT pathway can enhance muscle protein synthesis by activating GSK3β and mTOR. The IGF-1/PI3K/AKT pathway suppresses protein degradation, especially of myofibrillar proteins, and inhibits the expression of the key atrophy gene Atrogin-1, thus increasing protein synthesis [3, 5]. One of the downstream targets of the protein synthesis pathway PI3K/AKT is the Forkhead box O (FOXO) transcription factor class. FOXO is a subfamily of the forkhead transcription factors. Mammalian cells contain three members of this family: Foxo1 (FKHR), Foxo3 (FKHRL1), and FOXO4 (AFX) [6]. Various studies suggest that the gene expression of Atrogin-1 and MuRF1 is differentially regulated by FOXO and NF-κB pathways [4, 7-9]. The IGF-1/PI3K/AKT pathway, by inhibiting FOXO, prevents the upregulation of Atrogin-1 and suppresses muscle atrophy, while FOXO activation alone can induce acute atrophy of myotubes and mature muscle fibers. FOXO3 activation is both a sufficient and necessary condition for rapid atrophy. FOXO3 is the primary transcription factor driving the expression of most atrophy genes, promoting overall protein hydrolysis [6, 10]. Atrogin-1 and MuRF1 are significantly upregulated by FOXO3 in all muscle atrophy scenarios [11-13].
During the atrophy process, the degradation of myofibrillar and soluble proteins accelerates, and protein synthesis also diminishes, resulting in a rapid decline in muscle mass and weight, escalating frailty and disability levels. This situation reduces the quality of life and can even lead to increased mortality [14]. With the rise in chronic disease patients and extended life expectancy, healthy aging and independent living require maintaining muscle mass [15]. Therefore, there is now a more pressing need than ever to deeply understand the molecular mechanisms governing muscle mass and function.
3 Effect of ubiquitin-proteasome pathway on skeletal muscle atrophy
Currently, four protein degradation pathways have been identified in skeletal muscle atrophy: the Ubiquitin-Proteasome Pathway (UPS), the autophagy-lysosome system, the calcium-dependent calpain system, and the cysteine aspartate protease system [16-20]. The UPS is responsible for the specific degradation of most intracellular proteins and serves as an efficient protein degradation route. In cells, the vast majority of proteins are degraded through the ubiquitin-proteasome system, hence it plays a crucial role in the skeletal muscle atrophy process [20].
The Ubiquitin-Proteasome Pathway consists of ubiquitin and a series of related enzymes that degrade intracellular proteins. It is mainly composed of three parts: ubiquitin, ubiquitin-related enzymes, and the proteasome [21]. Ubiquitin (Ub) is present in all eukaryotes (most eukaryotic cells) and is a small protein composed of 76 amino acids with a molecular weight of approximately 8,500. Its primary function is to tag proteins requiring degradation, allowing them to be degraded by the 26S proteasome [22]. Ubiquitin can be reused and ubiquitination can be reversed by removing ubiquitin from target proteins through deubiquitinating enzymes (DUBS) [23, 24]. Ubiquitin-related enzymes include E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, E3 ubiquitin ligase, E4 ubiquitin chain extension enzyme, and deubiquitinating enzymes. Ubiquitin tagging of natively folded proteins is achieved through the first three enzymes. E3 ubiquitin ligase, a specific substrate-binding component, plays a pivotal role in the ubiquitin-mediated protein degradation cascade, determining the specificity and rate of UPS. The E3 ligase undergoes autoubiquitination, making it susceptible to proteasomal degradation, necessitating continuous transcriptional replenishment [3, 23]. The 26S proteasome, the primary protease of the ubiquitin-proteasome system, degrades polyubiquitinated proteins into peptides [25]. It consists of a 20S proteasome and one or two 19S proteasomes. These regulatory factors, when combined, enhance proteasome activity and allow the proteasome to degrade substrate proteins marked by complex enzyme machinery by attaching ubiquitin (Ub) molecule chains. The 20S can only recognize and degrade unfolded/damaged/misfolded proteins, while the 19S can recognize ubiquitinated proteins and other potential substrates of the proteasome, unfolding target proteins into protein chains to pass through the 20S core protein. Subsequently, substrates are degraded into short peptides, polyubiquitin chains are degraded into free monomers by deubiquitinating enzymes (DUB), and the released ubiquitin can be reused by the E1 enzyme [26]. Various types of E1, E2, and E3 enzymes facilitate the ubiquitination of different types of target proteins. The ubiquitination of proteins consists of four steps: 1) E1 activates ATP-dependent ubiquitin. 2) Activated ubiquitin is transferred to the E2 ubiquitin carrier protein. 3) E2 transfers the activated ubiquitin portion to a protein substrate specifically bound to E3. In the case of RING finger ligases, the transfer is direct, while in the case of HECT domain ligases, ubiquitin first forms an additional thioester intermediate on E3, then transferred from E3 to the substrate. 4) The continuous ligation of the ubiquitin portion produces polyubiquitin chains, which serve as a binding signal for the downstream 26S proteasome, causing the target substrate to degrade into peptides [21, 22, 27].
The ubiquitin-proteasome system involves nearly 750 E3 and about 90 DUB genes playing regulatory roles in skeletal muscle atrophy, referred to as atrogenes [28]. These atrogenes regulate various processes controlling muscle mass (such as myogenesis, protein synthesis, and degradation) and function in upstream regulatory pathways. These USP genes can be divided into three functions: 1) myofibril protein degradation, 2) myogenesis inhibition, and 3) autophagy regulation. During the ubiquitination process, E3 ligases are considered key enzymes catalyzing the activated form of Ub. Since their discovery in 2001, two muscle-specific E3 ubiquitin ligases, MuRF-1 and Atrogin-1 (MAFbx), have been shown to be associated with the regulation of skeletal muscle atrophy under various pathological and physiological conditions [29]. In mammalian muscles, MuRF1 and Atrogin-1 are responsible for the activation of protein degradation. Atrogin-1 and MuRF1 control the ubiquitination and subsequent forced degradation of regulatory proteins such as calcineurin phosphatase and MyoD as well as structural proteins like myosin and troponin I [3]. MuRF1 and Atrogin-1 are significantly upregulated during various types of atrophy. Additionally, inhibiting the expression of MuRF1 and Atrogin-1 can also partially counteract skeletal muscle atrophy [29-31].
3.1 The role of the ubiquitin-proteasome pathway in disuse muscle atrophy
The fundamental physiological principle of skeletal muscle is “use it or lose it.” Skeletal muscles exhibit significant plasticity, adapting according to functional demands. A reduction or cessation in activity levels typically leads to muscle atrophy and metabolic dysfunctions. The loss of skeletal muscle mass resulting from a sudden decrease in muscle loading and inhibited neural activation is often termed “disuse muscle atrophy.” Classic models of disuse muscle atrophy include bed rest, joint immobilization, mechanical ventilation, spaceflight, and denervation [32]. Any loss in skeletal muscle mass fundamentally stems from a chronic imbalance between muscle protein synthesis and degradation rates [33]. Muscle atrophy arises when the equilibrium between protein synthesis and degradation is disrupted, usually manifested by inhibited protein synthesis and elevated protein degradation, regardless of the duration of disuse. The loss in strength is often more than twice the muscle size reduction [34]. While there’s some debate about which of these factors predominates, most literature indicates that during the early stages of disuse (up to 10 days), protein synthesis remains relatively constant, while protein degradation increases considerably [35, 36]. That is, enhanced protein degradation is the primary cause of atrophy. For prolonged disuse (more than 10 days), the relationship with protein degradation becomes unclear, with decreased protein synthesis becoming the primary reason for muscle atrophy. The ubiquitin-proteasome system is generally considered the most crucial protein degradation system under disuse conditions. Under disuse, the ubiquitin-proteasome system is primarily regulated by the cellular energy sensor, AMP-activated protein kinase (AMPK). The role of AMPK in protein regulation evolves as the duration of disuse extends.
Studies have shown that when muscles are active, growth ceases; during muscle activity, the anabolic signaling pathway and protein synthesis are inhibited [37]. Eukaryotic elongation factor 2 (eEF2) and AMPK can lead to the suppression of the mTORC1/p70S6K signaling pathway and reduced mRNA translation efficiency [38, 39]. Upon cessation of activity, both anabolic and catabolic metabolism are activated to maintain intracellular homeostasis. From the first day of unloading, changes in adenosine monophosphate (AMP) concentration, accumulation of carbohydrates (CHO), and increased reactive oxygen species (ROS) concentration trigger a signaling cascade, resulting in the upregulation of E3 ubiquitin ligases. These factors culminate in alterations in protein metabolism and myosin phenotypes. On the first day of disuse, AMPK is dephosphorylated due to increased ATP accumulation in antigravity muscles compared to pectoral muscles, disrupting the ATP/AMP dynamic equilibrium [40-43]. Dephosphorylated AMPK might activate protein kinase D (PKD), with activated PKD further increasing AMPK dephosphorylation [41, 44]. Concurrently, CHO accumulation may also contribute to AMPK dephosphorylation [45]. As AMPK activity diminishes, cytoplasmic calcium concentration drops, and dephosphorylated eEF2 stimulates polypeptide chain elongation, activating the anabolic pathway, thus enhancing muscle protein synthesis rate [38, 39, 46]. However, with prolonged muscle disuse (e.g., 4–5 days), reduced mitochondrial oxidative phosphorylation leads to decreased ATP production. Subsequently, activated AMPK can phosphorylate six regulatory sites on FOXO3, promoting its nuclear retention and activation [47, 48], leading to the upregulation of key atrophy genes Atrogin-1 and MuRF1, resulting in muscle atrophy. For even more extended disuse periods (>10 days), research suggests that muscle atrophy is primarily due to decreased protein synthesis rates, without a significant increase in protein degradation [33]. Additionally, reactive oxygen species (ROS), crucial regulators in cellular signaling pathways, coupled with compromised antioxidant systems, are often regarded as major inducers affecting disuse muscle atrophy protein synthesis and degradation [49-51]. Intracellular Ca2+ overload, by activating caspase-3-dependent apoptosis, is also an essential signaling pathway in disuse muscle atrophy [52].
Current research on countering disuse muscle atrophy suggests that exercise is among the best strategies. Existing literature confirms that different types of resistance exercises enhance muscle protein synthesis by activating the PI3K-AKT-mTOR pathway, playing a crucial role in disuse models [53-55]. However, exercise might not be suitable for the elderly or those bedridden for extended periods, and during spaceflight, exercise can only partially delay microgravity-induced skeletal muscle atrophy [56]. Preliminary studies in our laboratory suggest that Rhodiola rosea can effectively counteract microgravity-induced muscle atrophy. Traditional Chinese herbs like Astragalus, Schisandra, and taurine have been proven in studies to reduce the expression of ubiquitin ligases Atrogin-1 or MuRF1 and inhibit disuse muscle atrophy [57-59], hinting at the potential of traditional medicine as a promising approach against disuse muscle atrophy in the future. Resveratrol, an antioxidant, has successfully counteracted disuse atrophy in studies [60]. Additionally, while protein supplementation combined with exercise yields optimal results, amino acid supplementation alone can notably improve protein synthesis but can only partially counteract muscle atrophy [61].
In conclusion, the primary cause of disuse muscle atrophy might be the skeletal muscle’s adaptive self-regulation in response to low energy consumption. Hence, mere energy supplementation might be the least effective remedy for disuse muscle atrophy; short-term disuse is mainly due to increased protein degradation, while long-term disuse relies on reduced protein synthesis. The combination of exercise and amino acid supplementation stands out as the best countermeasure for disuse muscle atrophy, with various traditional medicines and antioxidants demonstrating promising therapeutic potentials.
3.2 The role of the ubiquitin-proteasome pathway in sarcopenia
Sarcopenia is the age-related loss of skeletal muscle mass and function [62]. As age advances, numerous changes occur in skeletal muscle, such as the transformation of type II muscle fibers to type I, infiltration of fat within and between muscles, a decrease in the number of type II fiber satellite cells, and alterations in the integrity of mitochondria in muscle cells [63-67]. Aging disrupts the homeostasis of skeletal muscle, leading to an imbalance in the pathways of muscle protein synthesis and degradation, resulting in comprehensive muscle atrophy [68]. Concurrently, elderly individuals are prone to bedridden conditions due to illness, thus facing the dual challenges of disuse muscle atrophy and sarcopenia. A study by Landi and colleagues using the EWGSOP assessment method on individuals over 80 years old revealed that muscle loss syndrome is prevalent among the elderly (25%), and the risk of falls for these patients during a 2-year follow-up period is more than three times that of non-sarcopenic patients [69]. A study by Kitamura Akira indicated that the prevalence of sarcopenia among Asian men is 11.5%, and 16.7% among women [70]. Another study on sarcopenia suggested that the mortality risk for men depends on muscle mass, while for women, the risk is more influenced by low fat mass, muscle strength, and physical performance [71]. Given the growing aging population, combatting sarcopenia has become an urgent issue.
The 2018 International Clinical Practice Guidelines for Sarcopenia (ICFSR) highlighted that physical activity combined with resistance training can be the primary prescription for treating sarcopenia [72]. Steven’s research suggests that resistance and endurance exercises three times a week can significantly benefit sarcopenia by improving muscle mass, strength, and function. There are few exercise experiments designed specifically for sarcopenia patients, and the methods, durations, and intensities vary, but all have demonstrated the effectiveness of exercise against sarcopenia [73-75]. Some evidence suggests that adequate intake of protein, vitamin D, antioxidants, and long-chain polyunsaturated fatty acids is beneficial for health [76], but their individual effects on sarcopenia have not been reported. Nevertheless, protein and vitamin D supplements remain essential components for sarcopenia treatment. Alfonso reported that essential amino acid (EAA) leucine and β-hydroxy-β-methylbutyrate (HMB) supplements have a role in improving muscle mass and function [77]. Currently, no specific drugs have been approved for sarcopenia. Aging is accompanied by a reduction in testosterone and growth hormone secretion. A report by Manthos revealed that the combined administration of testosterone and growth hormone is more effective than either hormone alone [78]. A recent study suggested that inhibiting muscle growth inhibitors might be a new direction to combat sarcopenia [79].
Early studies found that the ubiquitin levels in the extensor digitorum longus (EDL) of elderly rats (24 months old) and the quadriceps of humans aged 70–79 years were significantly increased compared to normal levels [80]. Recently, some researchers detected that the overall ubiquitin level in rat bicep femoris muscle increases with age [81]. However, contradicting findings have emerged. A study by Leslie showed no difference in the overall ubiquitin levels in the bicep femoris muscles of 9-month-old and 29-month-old male rats[^82^]. The role of Atrogin-1 and MuRF1 in sarcopenia research has shown conflicting results. In Clavel’s report, the mRNA levels of Atrogin-1 and MuRF1 in the tibialis anterior (TA) muscle of 24-month-old rats significantly increased compared to 5-month-old controls [83]. Other studies reported either unchanged or decreased levels of Atrogin-1 and MuRF1 [82, 84]. Darren and colleagues found that knocking out the MuRF1 gene in 24-month-old mice resulted in a significant reduction in muscle weight, strength, and cross-sectional area (CSA) compared to controls[85]. Some found that the lifespan of Atrogin-1 knockout mice is shorter than normal mice, and they experience higher muscle mass loss during aging [86], suggesting that E3 ubiquitin ligases play a crucial role in maintaining muscle mass during mouse aging.
In summary, in studies related to age-associated skeletal muscle atrophy, both exercise and hormonal or drug therapies have demonstrated effectiveness against atrophy. However, research on their development and combat mechanisms, especially concerning the ubiquitin pathway, is limited, and findings have been inconsistent. This illustrates the complexity of the causes of sarcopenia and suggests a need for further research to clarify the mechanisms underlying the onset of sarcopenia.
3.3 The role of the ubiquitin-proteasome pathway in cancer cachexia
Cancer Cachexia (CaCax), often simply referred to as cachexia, is a severe complication of cancer. Approximately one-third of cancer-related deaths can be attributed to cachexia [87]. It is characterized by progressive atrophy of skeletal muscles and adipose tissues, weight loss, decline in quality of life, and reduced life expectancy [88, 89]. Studies have indicated that cachexia cannot be prevented or alleviated by mere dietary changes or nutritional augmentation [90]. Multiple experiments have demonstrated that inhibiting skeletal muscle atrophy in cachexia patients can significantly prolong their lifespan [91, 92]. Thus, the prevention and treatment of cachexia might be an essential prerequisite for treating cancer patients.
Distinct from other types of muscle atrophy, a hallmark of cancer cachexia is pervasive systemic inflammation [93, 94]. Inflammatory cytokines regulate the intracellular signaling pathways associated with muscle atrophy. In vitro studies suggest that these cytokines can elevate the expression of muscle-specific ubiquitin ligases, Atrogin-1 and MuRF1. Pro-inflammatory cytokines partly induce muscle atrophy by modulating the AKT/FOXO/UPS pathway. Phosphorylation of AKT inhibits protein catabolism transcription factors. The full activation of AKT, which promotes protein synthesis and induces FOXO1, initially accelerates protein degradation and contributes to MuRF1 and Atrogin-1 transcription during muscle atrophy. Pro-inflammatory cytokine Interleukin-6 (IL-6) is considered a central mediator of cancer cachexia, with IL-6 levels correlating positively with the progression of cachexia [95]. Baltgalvis et al. found that in cancer mice, systemic concentrations of IL-6 increased with tumor progression and correlated with elevated p-STAT-3 and Atrogin-1 mRNA levels [96]. Research indicates that IL-6 binds with the IL-6r-Gp130 receptor complex and activates the JAK tyrosine kinase. Conformational changes in JAK proteins activate the STAT proteins through phosphorylation [97]. STAT transcriptional activation induces muscle atrophy through various mechanisms. STAT stimulates the activity of CCAAT/enhancer-binding protein (C/EBPδ), thereby enhancing the expression of myostatin, Atrogin-1, MuRF1, and caspase-3 [98, 99]. Furthermore, in cachexia-induced muscle atrophy, inflammation can suppress IGF-1, leading to enhanced catabolism [100]. IGF-1 is a pivotal growth factor regulating both the anabolic and catabolic pathways of skeletal muscle. Inhibiting the IGF-1/PI3K/AKT pathway results in protein degradation, particularly of myofibrillar proteins, and an increased expression of Atrogin-1 [3, 5, 101]. Even though inflammation has been proven to play a crucial role in the development of cachexia, more insight is needed into how these cytokines advance disease progression to either prevent or delay cachexia’s onset.
In conclusion, substantial evidence from both animal and human studies suggests that the UPS is activated during skeletal muscle atrophy in cancer cachexia. Muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 are notably upregulated during the onset and progression of cancer cachexia, with inflammation playing a pivotal role in the development of muscle atrophy in cachexia. Due to the complex etiology of diseases like cancer, no effective measures have been identified to counteract the muscle atrophy they induce. Hence, there’s a pressing need for further research into the role of UPS in skeletal muscle atrophy during cancer cachexia in humans.
4 Summary and outlook
Historically, the physiological challenge posed by skeletal muscle atrophy has been of paramount importance. Its implications span across the potential extension of human lifespan, advances in cancer treatment, and even the bold aspirations of interstellar exploration. The struggle against skeletal muscle atrophy has, and continues to be, a pressing matter in the annals of scientific inquiry.
Contemporary research delineates that while every decrement in skeletal muscle mass is invariably anchored in a persistent disequilibrium between muscle protein synthesis and degradation, muscle atrophy, dependent on its etiology, manifests distinct pathophysiological characteristics. Disuse muscle atrophy, for instance, can largely be ascribed to metabolic adaptations to diminished energy demands, and interventions such as resistance training coupled with amino acid supplementation emerge as primary counteractive measures. In the realm of age-induced muscle atrophy, modalities ranging from exercise regimens to hormonal therapeutics have been spotlighted for their potential therapeutic benefits. When navigating the complexities of cancer cachexia, the omnipresent shadow of inflammation looms large, underpinning muscle wasting processes. Despite cachexia’s multifarious etiological landscape, therapeutically targeting inflammation presents itself as an imperative.
Yet, within the corpus of extant literature, the exploration of the ubiquitin-proteasome system (UPS) in skeletal muscle atrophy remains, surprisingly, in its nascent stages. Elevated expressions of diverse E3 ligases have been identified across various atrophic conditions. Inhibition of the UPS pathway offers a tantalizing prospect for mitigating muscle wasting. However, a mosaic of experimental results has emerged, with some indicating that certain E3 gene knockouts neither halt nor alleviate muscle atrophy, and might even accentuate its progression. Thus, the labyrinth of UPS in skeletal muscle atrophy’s mechanistic underpinnings is yet to be fully navigated. Seminal studies, notably those centered around MuRF1 and Atrogin-1, pave the way, but the journey ahead mandates a deeper scholarly quest to unveil precise mechanisms, thereby fortifying our theoretical armamentarium for muscle atrophy’s prevention and treatment.
Author contributions
XP: Writing–original draft, Writing–review and editing. PZ: Writing–review and editing. XC: Writing–review and editing. WL: Writing–review and editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the grants from the National Natural Science Foundation of China (32171173) and the Manned space engineering space medical experimental field project (HYZHXM01017).
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.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Adams V., Schauer A., Augstein A., Kirchhoff V., Draskowski R., Jannasch A., et al. (2022). Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility. J. Cachexia, Sarcopenia Muscle 13 (3), 1565–1581. doi:10.1002/jcsm.12968
Angulo J., El Assar M., Rodriguez-Manas L. (2016). Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults. Mol. Aspects Med. 50, 1–32. doi:10.1016/j.mam.2016.06.001
Baehr L. M., West D. W. D., Marcotte G., Marshall A. G., De Sousa L. G., Baar K., et al. (2016). Age-related deficits in skeletal muscle recovery following disuse are associated with neuromuscular junction instability and ER stress, not impaired protein synthesis. Aging 8 (1), 127–146. doi:10.18632/aging.100879
Baehr L. M., West D. W. D., Marshall A. G., Marcotte G. R., Baar K., Bodine S. C. (2017). Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats. J. Appl. physiology (Bethesda, Md, 1985) 122 (5), 1336–1350. doi:10.1152/japplphysiol.00703.2016
Baldwin K. M., Haddad F., Pandorf C. E., Roy R. R., Edgerton V. R. (2013). Alterations in muscle mass and contractile phenotype in response to unloading models: role of transcriptional/pretranslational mechanisms. Front. Physiology 4, 284. doi:10.3389/fphys.2013.00284
Baltgalvis K. A., Berger F. G., Peña M. M. O., Davis J. M., White J. P., Carson J. A. (2009). Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc (Min/+) mouse. Pflugers Archiv Eur. J. physiology 457 (5), 989–1001. doi:10.1007/s00424-008-0574-6
Bartoli M., Richard I. (2005). Calpains in muscle wasting. Int. J. Biochem. Cell Biol. 37 (10), 2115–2133. doi:10.1016/j.biocel.2004.12.012
Bodine S. C., Latres E., Baumhueter S., Lai V. K., Nunez L., Clarke B. A., et al. (2001). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294 (5547), 1704–1708. doi:10.1126/science.1065874
BodineAdolph Distinguished Lecture S. C. E. F. (2020). Edward F. Adolph Distinguished Lecture. Skeletal muscle atrophy: multiple pathways leading to a common outcome. J. Appl. physiology (Bethesda, Md, 1985) 129 (2), 272–282. doi:10.1152/japplphysiol.00381.2020
Bonetto A., Aydogdu T., Kunzevitzky N., Guttridge D. C., Khuri S., Koniaris L. G., et al. (2011). STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. Plos One 6 (7), e22538. doi:10.1371/journal.pone.0022538
Cai D., Lee K. K. H., Li M., Tang M. K., Chan K. M. (2004). Ubiquitin expression is up-regulated in human and rat skeletal muscles during aging. Archives Biochem. biophysics 425 (1), 42–50. doi:10.1016/j.abb.2004.02.027
Chen C.-N., Liao Y.-H., Tsai S.-C., Thompson L. V. (2019). Age-dependent effects of caloric restriction on mTOR and ubiquitin-proteasome pathways in skeletal muscles. Geroscience 41 (6), 871–880. doi:10.1007/s11357-019-00109-8
Chibalin A. V., Benziane B., Zakyrjanova G. F., Kravtsova V. V., Krivoi I. I. (2018). Early endplate remodeling and skeletal muscle signaling events following rat hindlimb suspension. J. Cell. Physiology 233 (10), 6329–6336. doi:10.1002/jcp.26594
Cho S., Hong R., Yim P., Yeom M., Lee B., Yang W. M., et al. (2018). An herbal formula consisting of Schisandra chinensis (Turcz.) Baill, Lycium chinense Mill and Eucommia ulmoides Oliv alleviates disuse muscle atrophy in rats. J. Ethnopharmacol. 213, 328–339. doi:10.1016/j.jep.2017.10.008
Ciciliot S., Rossi A. C., Dyar K. A., Blaauw B., Schiaffino S. (2013). Muscle type and fiber type specificity in muscle wasting. Int. J. Biochem. Cell Biol. 45 (10), 2191–2199. doi:10.1016/j.biocel.2013.05.016
Ciechanover A. (2005). Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture). Angew. Chem. Int. Ed. Engl. 44 (37), 5944–5967. doi:10.1002/anie.200501428
Ciechanover A. (2006). The ubiquitin proteolytic system: from a vague idea, through basic mechanisms, and onto human diseases and drug targeting. Neurology 66 (2 Suppl. 1), S7–S19. doi:10.1212/01.wnl.0000192261.02023.b8
Ciechanover A. (2012). Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Biochimica biophysica acta 1824 (1), 3–13. doi:10.1016/j.bbapap.2011.03.007
Clavel S., Coldefy A.-S., Kurkdjian E., Salles J., Margaritis I., Derijard B. (2006). Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle. Mech. Ageing Dev. 127 (10), 794–801. doi:10.1016/j.mad.2006.07.005
Cohen S., Nathan J. A., Goldberg A. L. (2015). Muscle wasting in disease: molecular mechanisms and promising therapies. Nat. Rev. Drug Discov. 14 (1), 58–74. doi:10.1038/nrd4467
Correa-de-Araujo R., Harris-Love M. O., Miljkovic I., Fragala M. S., Anthony B. W., Manini T. M. (2017). The need for standardized assessment of muscle quality in skeletal muscle function deficit and other aging-related muscle dysfunctions: a symposium report. Front. Physiology 8, 87. doi:10.3389/fphys.2017.00087
Cruz-Jentoft A. J., Landi F., Schneider S. M., Zúñiga C., Arai H., Boirie Y., et al. (2014). Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing 43 (6), 748–759. doi:10.1093/ageing/afu115
Cruz-Jentoft A. J., Sayer A. A. (2019). Sarcopenia. Lancet 393 (10191), 2636–2646. doi:10.1016/S0140-6736(19)31138-9
Demontis G. C., Germani M. M., Caiani E. G., Barravecchia I., Passino C., Angeloni D. (2017). Human pathophysiological adaptations to the space environment. Front. Physiol. 8, 547. doi:10.3389/fphys.2017.00547
Dent E., Morley J. E., Cruz-Jentoft A. J., Arai H., Kritchevsky S. B., Guralnik J., et al. (2018). International clinical Practice Guidelines for sarcopenia (ICFSR): screening, diagnosis and management. J. Nutr. Health Aging 22 (10), 1148–1161. doi:10.1007/s12603-018-1139-9
Deutz N. E. P., Bauer J. M., Barazzoni R., Biolo G., Boirie Y., Bosy-Westphal A., et al. (2014). Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group. Clin. Nutr. 33 (6), 929–936. doi:10.1016/j.clnu.2014.04.007
Dikic I., Wakatsuki S., Walters K. J. (2009). Ubiquitin-binding domains - from structures to functions. Nat. Rev. Mol. Cell Biol. 10 (10), 659–671. doi:10.1038/nrm2767
Dreyer H. C., Fujita S., Cadenas J. G., Chinkes D. L., Volpi E., Rasmussen B. B. (2006). Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J. Physiology 576 (Pt 2), 613–624. doi:10.1113/jphysiol.2006.113175
Du J., Wang X., Miereles C., Bailey J. L., Debigare R., Zheng B., et al. (2004). Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J. Clin. Invest. 113 (1), 115–123. doi:10.1172/JCI18330
Dutt V., Gupta S., Dabur R., Injeti E., Mittal A. (2015). Skeletal muscle atrophy: potential therapeutic agents and their mechanisms of action. Pharmacol. Res. 99, 86–100. doi:10.1016/j.phrs.2015.05.010
Ferrando A. A., Tipton K. D., Bamman M. M., Wolfe R. R. (1997). Resistance exercise maintains skeletal muscle protein synthesis during bed rest. J. Appl. physiology (Bethesda, Md, 1985) 82 (3), 807–810. doi:10.1152/jappl.1997.82.3.807
Fielding R. A., Vellas B., Evans W. J., Bhasin S., Morley J. E., Newman A. B., et al. (2011). Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J. Am. Med. Dir. Assoc. 12 (4), 249–256. doi:10.1016/j.jamda.2011.01.003
Fluckey J. D., Dupont-Versteegden E. E., Knox M., Gaddy D., Tesch P. A., Peterson C. A. (2004). Insulin facilitation of muscle protein synthesis following resistance exercise in hindlimb-suspended rats is independent of a rapamycin-sensitive pathway. Am. J. Physiology. Endocrinol. Metabolism 287 (6), E1070–E1075. doi:10.1152/ajpendo.00329.2004
Frontera W. R., Zayas A. R., Rodriguez N. (2012). Aging of human muscle: understanding sarcopenia at the single muscle cell level. Phys. Med. Rehabilitation Clin. N. Am. 23 (1), 201–207. doi:10.1016/j.pmr.2011.11.012
Giannoulis M. G., Martin F. C., Nair K. S., Umpleby A. M., Sonksen P. (2012). Hormone replacement therapy and physical function in healthy older men. Time to talk hormones? Endocr. Rev. 33 (3), 314–377. doi:10.1210/er.2012-1002
Glover E. I., Phillips S. M., Oates B. R., Tang J. E., Tarnopolsky M. A., Selby A., et al. (2008). Immobilization induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion. J. Physiology 586 (24), 6049–6061. doi:10.1113/jphysiol.2008.160333
Gustafsson T., Osterlund T., Flanagan J. N., von Waldén F., Trappe T. A., Linnehan R. M., et al. (2010). Effects of 3 days unloading on molecular regulators of muscle size in humans. J. Appl. physiology (Bethesda, Md, 1985) 109 (3), 721–727. doi:10.1152/japplphysiol.00110.2009
Haberecht-Müller S., Krüger E., Fielitz J. (2021). Out of control: the role of the ubiquitin proteasome system in skeletal muscle during inflammation. Biomolecules 11 (9), 1327. doi:10.3390/biom11091327
Hameed D. S., Sapmaz A., Ovaa H. (2017). How chemical synthesis of ubiquitin conjugates helps to understand ubiquitin signal transduction. Bioconjug Chem. 28 (3), 805–815. doi:10.1021/acs.bioconjchem.6b00140
Han H. Q., Zhou X., Mitch W. E., Goldberg A. L. (2013). Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int. J. Biochem. Cell Biol. 45 (10), 2333–2347. doi:10.1016/j.biocel.2013.05.019
Henriksen E. J., Tischler M. E. (1988). Time course of the response of carbohydrate metabolism to unloading of the soleus. Metabolism 37 (3), 201–208. doi:10.1016/0026-0495(88)90096-0
Hwee D. T., Baehr L. M., Philp A., Baar K., Bodine S. C. (2014). Maintenance of muscle mass and load-induced growth in Muscle RING Finger 1 null mice with age. Aging Cell 13 (1), 92–101. doi:10.1111/acel.12150
Ji L. L., Yeo D., Kang C. (2020). Muscle disuse atrophy caused by discord of intracellular signaling. Antioxid. Redox Signal 33 (11), 727–744. doi:10.1089/ars.2020.8072
Jung T., Grune T. (2013). The proteasome and the degradation of oxidized proteins: Part I-structure of proteasomes. Redox Biol. 1, 178–182. doi:10.1016/j.redox.2013.01.004
Kalyani R. R., Corriere M., Ferrucci L. (2014). Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol. 2 (10), 819–829. doi:10.1016/S2213-8587(14)70034-8
Khalil R. (2018). Ubiquitin-proteasome pathway and muscle atrophy. Muscle Atrophy 1088, 235–248. doi:10.1007/978-981-13-1435-3_10
Khalil R. M., Abdo W. S., Saad A., Khedr E. G. (2018). Muscle proteolytic system modulation through the effect of taurine on mice bearing muscular atrophy. Mol. Cell Biochem. 444 (1-2), 161–168. doi:10.1007/s11010-017-3240-5
Kimball S. R. (2006). Interaction between the AMP-activated protein kinase and mTOR signaling pathways. Med. Sci. sports Exerc. 38 (11), 1958–1964. doi:10.1249/01.mss.0000233796.16411.13
Kisselev A. F., Goldberg A. L. (2001). Proteasome inhibitors: from research tools to drug candidates. Chem. Biol. 8 (8), 739–758. doi:10.1016/s1074-5521(01)00056-4
Kitamura A., Seino S., Abe T., Nofuji Y., Yokoyama Y., Amano H., et al. (2021). Sarcopenia: prevalence, associated factors, and the risk of mortality and disability in Japanese older adults. J. Cachexia Sarcopenia Muscle 12 (1), 30–38. doi:10.1002/jcsm.12651
Landi F., Liperoti R., Russo A., Giovannini S., Tosato M., Capoluongo E., et al. (2012). Sarcopenia as a risk factor for falls in elderly individuals: results from the ilSIRENTE study. Clin. Nutr. 31 (5), 652–658. doi:10.1016/j.clnu.2012.02.007
Lecker S. H., Solomon V., Mitch W. E., Goldberg A. L. (1999). Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J. Nutr. 129 (1S Suppl. l), 227S-237S–237S. doi:10.1093/jn/129.1.227S
Levine S., Biswas C., Dierov J., Barsotti R., Shrager J. B., Nguyen T., et al. (2011). Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human diaphragm disuse. Am. J. Respir. Crit. Care Med. 183 (4), 483–490. doi:10.1164/rccm.200910-1487OC
Liu X., Yu R., Sun L., Garibotto G., Lin X., Wang Y., et al. (2017). The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease. Kidney Int. 92 (2), 336–348. doi:10.1016/j.kint.2017.02.031
Martín A. I., Priego T., Moreno-Ruperez Á., González-Hedström D., Granado M., López-Calderón A. (2021). IGF-1 and IGFBP-3 in inflammatory cachexia. Int. J. Mol. Sci. 22 (17), 9469. doi:10.3390/ijms22179469
McGee S. L., Swinton C., Morrison S., Gaur V., Campbell D. E., Jorgensen S. B., et al. (2014). Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol. 28 (8), 3384–3395. doi:10.1096/fj.14-249359
Mirzoev T., Tyganov S., Vilchinskaya N., Lomonosova Y., Shenkman B. (2016). Key markers of mTORC1-dependent and mTORC1-independent signaling pathways regulating protein synthesis in rat soleus muscle during early stages of hindlimb unloading. Cell. Physiology Biochem. Int. J. Exp. Cell. Physiology, Biochem. Pharmacol. 39 (3), 1011–1020. doi:10.1159/000447808
Momken I., Stevens L., Bergouignan A., Desplanches D., Rudwill F., Chery I., et al. (2011). Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol. 25 (10), 3646–3660. doi:10.1096/fj.10-177295
Moresi V., Adamo S., Berghella L. (2019). The JAK/STAT pathway in skeletal muscle pathophysiology. Front. Physiology 10, 500. doi:10.3389/fphys.2019.00500
Murton A. J., Constantin D., Greenhaff P. L. (2008). The involvement of the ubiquitin proteasome system in human skeletal muscle remodelling and atrophy. Biochimica biophysica acta 1782 (12), 730–743. doi:10.1016/j.bbadis.2008.10.011
Muscaritoli M., Anker S. D., Argiles J., Aversa Z., Bauer J. M., Biolo G., et al. (2010). Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clin. Nutr. 29 (2), 154–159. doi:10.1016/j.clnu.2009.12.004
Nozaki R., Hung Y. L., Takagi K., Nakano D., Fujii T., Kawanishi N., et al. (2020). Differential protective effects of Radix astragali, herbal medicine, on immobilization-induced atrophy of slow-twitch and fast-twitch muscles. Biomed. Res. 41 (3), 139–148. doi:10.2220/biomedres.41.139
Oyabu M., Takigawa K., Mizutani S., Hatazawa Y., Fujita M., Ohira Y., et al. (2022). FOXO1 cooperates with C/EBPδ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol. 36 (2), e22152. doi:10.1096/fj.202101385rr
Pasiakos S. M., Carbone J. W. (2014). Assessment of skeletal muscle proteolysis and the regulatory response to nutrition and exercise. IUBMB Life 66 (7), 478–484. doi:10.1002/iub.1291
Peris-Moreno D., Cussonneau L., Combaret L., Polge C., Taillandier D. (2021). Ubiquitin ligases at the heart of skeletal muscle atrophy control. Mol. (Basel, Switz. 26 (2), 407. doi:10.3390/molecules26020407
Petruzzelli M., Schweiger M., Schreiber R., Campos-Olivas R., Tsoli M., Allen J., et al. (2014). A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20 (3), 433–447. doi:10.1016/j.cmet.2014.06.011
Philp A., Hamilton D. L., Baar K. (2011). Signals mediating skeletal muscle remodeling by resistance exercise: PI3-kinase independent activation of mTORC1. J. Appl. physiology (Bethesda, Md, 1985) 110 (2), 561–568. doi:10.1152/japplphysiol.00941.2010
Phu S., Boersma D., Duque G. (2015). Exercise and sarcopenia. J. Clin. Densitom. 18 (4), 488–492. doi:10.1016/j.jocd.2015.04.011
Picca A., Calvani R., Bossola M., Allocca E., Menghi A., Pesce V., et al. (2018). Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia. Biol. Chem. 399 (5), 421–436. doi:10.1515/hsz-2017-0331
Powers S. K. (2014). Can antioxidants protect against disuse muscle atrophy? Sports Med. Auckl. N.Z.) 44 (2), S155–S165. doi:10.1007/s40279-014-0255-x
Powers S. K., Kavazis A. N., DeRuisseau K. C. (2005). Mechanisms of disuse muscle atrophy: role of oxidative stress. Am. J. Physiology. Regul. Integr. Comp. Physiology 288 (2), R337–R344. doi:10.1152/ajpregu.00469.2004
Rausch V., Sala V., Penna F., Porporato P. E., Ghigo A. (2021). Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia. Oncogenesis 10 (1), 1. doi:10.1038/s41389-020-00288-6
Rennie M. J. (2005). Why muscle stops building when it's working. J. Physiology 569 (Pt 1), 3. doi:10.1113/jphysiol.2005.099424
Robinson S. M., Reginster J. Y., Rizzoli R., Shaw S. C., Kanis J. A., Bautmans I., et al. (2018). Does nutrition play a role in the prevention and management of sarcopenia? Clin. Nutr. Edinb. Scotl. 37 (4), 1121–1132. doi:10.1016/j.clnu.2017.08.016
Rom O., Reznick A. Z. (2016). The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass. Free Radic. Biol. Med. 98, 218–230. doi:10.1016/j.freeradbiomed.2015.12.031
Romanello V., Sandri M. (2015). Mitochondrial quality control and muscle mass maintenance. Front. Physiol. 6, 422. doi:10.3389/fphys.2015.00422
Rooks D., Praestgaard J., Hariry S., Laurent D., Petricoul O., Perry R. G., et al. (2017). Treatment of sarcopenia with bimagrumab: results from a phase II, randomized, controlled, proof-of-concept study. J. Am. Geriatrics Soc. 65 (9), 1988–1995. doi:10.1111/jgs.14927
Rose A. J., Alsted T. J., Jensen T. E., Kobberø J. B., Maarbjerg S. J., Jensen J., et al. (2009). A Ca(2+)-calmodulin-eEF2K-eEF2 signalling cascade, but not AMPK, contributes to the suppression of skeletal muscle protein synthesis during contractions. J. Physiology 587 (Pt 7), 1547–1563. doi:10.1113/jphysiol.2008.167528
Sanchez A. M. J., Candau R. B., Csibi A., Pagano A. F., Raibon A., Bernardi H. (2012). The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis. Am. J. Physiology. Cell Physiology 303 (5), C475–C485. doi:10.1152/ajpcell.00125.2012
Sandri M., Barberi L., Bijlsma A. Y., Blaauw B., Dyar K. A., Milan G., et al. (2013). Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 14 (3), 303–323. doi:10.1007/s10522-013-9432-9
Sandri M., Lin J., Handschin C., Yang W., Arany Z. P., Lecker S. H., et al. (2006). PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl. Acad. Sci. U. S. A. 103 (44), 16260–16265. doi:10.1073/pnas.0607795103
Segalés J., Perdiguero E., Serrano A. L., Sousa-Victor P., Ortet L., Jardí M., et al. (2020). Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals. Nat. Commun. 11 (1), 189. doi:10.1038/s41467-019-13832-9
Seino S., Kitamura A., Abe T., Nofuji Y., Yokoyama Y., Amano H., et al. (2022). Sarcopenia: prevalence, associated factors, and the risk of mortality and disability in Japanese older adults. J. Cachexia Sarcopenia Muscle 13 (2), 30–38. doi:10.1002/jcsm.12651
Seto D. N., Kandarian S. C., Jackman R. W. (2015). A key role for leukemia inhibitory factor in C26 cancer cachexia. J. Biol. Chem. 290 (32), 19976–19986. doi:10.1074/jbc.M115.638411
Silva K. A., Dong J., Dong Y., Schor N., Tweardy D. J., Zhang L., et al. (2015). Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. J. Biol. Chem. 290 (17), 11177–11187. doi:10.1074/jbc.M115.641514
Silveira W. A., Goncalves D. A., Machado J., Lautherbach N., Lustrino D., Paula-Gomes S., et al. (2020). cAMP-dependent protein kinase inhibits FoxO activity and regulates skeletal muscle plasticity in mice. FASEB J. official Publ. Fed. Am. Soc. Exp. Biol. 34 (9), 12946–12962. doi:10.1096/fj.201902102RR
Sinam I. S., Chanda D., Thoudam T., Kim M. J., Kim B. G., Kang H. J., et al. (2022). Pyruvate dehydrogenase kinase 4 promotes ubiquitin-proteasome system-dependent muscle atrophy. J. Cachexia, Sarcopenia Muscle 13 (6), 3122–3136. doi:10.1002/jcsm.13100
Sirago G., Pellegrino M. A., Bottinelli R., Franchi M. V., Narici M. V. (2022). Loss of neuromuscular junction integrity and muscle atrophy in skeletal muscle disuse. Ageing Res. Rev. 83, 101810. doi:10.1016/j.arr.2022.101810
Talbert E. E., Smuder A. J., Min K., Kwon O. S., Powers S. K. (2013). Calpain and caspase-3 play required roles in immobilization-induced limb muscle atrophy. J. Appl. physiology (Bethesda, Md, 1985) 114 (10), 1482–1489. doi:10.1152/japplphysiol.00925.2012
Tang H., Inoki K., Lee M., Wright E., Khuong A., Khuong A., et al. (2014). mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases. Sci. Signal. 7 (314), ra18. doi:10.1126/scisignal.2004809
Tesch P. A., Lundberg T. R., Fernandez-Gonzalo R. (2016). Unilateral lower limb suspension: from subject selection to "omic" responses. J. Appl. physiology (Bethesda, Md, 1985) 120 (10), 1207–1214. doi:10.1152/japplphysiol.01052.2015
Verdijk L. B., Snijders T., Drost M., Delhaas T., Kadi F., van Loon L. J. C. (2014). Satellite cells in human skeletal muscle; from birth to old age. Age Dordr. Neth. 36 (2), 545–547. doi:10.1007/s11357-013-9583-2
Vilchinskaya N. A., Mochalova E. P., Nemirovskaya T. L., Mirzoev T. M., Turtikova O. V., Shenkman B. S. (2017). Rapid decline in MyHC I(β) mRNA expression in rat soleus during hindlimb unloading is associated with AMPK dephosphorylation. J. Physiology 595 (23), 7123–7134. doi:10.1113/JP275184
von Haehling S., Anker S. D. (2010). Cachexia as a major underestimated and unmet medical need: facts and numbers. J. Cachexia, Sarcopenia Muscle 1 (1), 1–5. doi:10.1007/s13539-010-0002-6
Wakatsuki T., Ohira Y., Yasui W., Nakamura K., Asakura T., Ohno H., et al. (1994). Responses of contractile properties in rat soleus to high-energy phosphates and/or unloading. Jpn. J. Physiology 44 (2), 193–204. doi:10.2170/jjphysiol.44.193
Wall B. T., Dirks M. L., van Loon L. J. (2013). Skeletal muscle atrophy during short-term disuse: implications for age-related sarcopenia. Ageing Res. Rev. 12 (4), 898–906. doi:10.1016/j.arr.2013.07.003
Webb A. E., Brunet A. (2014). FOXO transcription factors: key regulators of cellular quality control. Trends Biochem. Sci. 39 (4), 159–169. doi:10.1016/j.tibs.2014.02.003
Zhang L., Pan J., Dong Y., Tweardy D. J., Garibotto G., Mitch W. E., et al. (2013). Stat3 activation links a C/EBPδ to myostatin pathway to stimulate loss of muscle mass. Cell Metab. 18 (3), 368–379. doi:10.1016/j.cmet.2013.07.012
Zhao J., Brault J. J., Schild A., Cao P., Sandri M., Schiaffino S., et al. (2007). FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6 (6), 472–483. doi:10.1016/j.cmet.2007.11.004
Zhou X., Wang J. L., Lu J., Song Y., Kwak K. S., Jiao Q., et al. (2010). Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142 (4), 531–543. doi:10.1016/j.cell.2010.07.011
Keywords: skeletal muscle atrophy, ubiquitin-proteasom, muscle disuse, sarcopenia, cachexia
Citation: Pang X, Zhang P, Chen X and Liu W (2023) Ubiquitin-proteasome pathway in skeletal muscle atrophy. Front. Physiol. 14:1289537. doi: 10.3389/fphys.2023.1289537
Received: 06 September 2023; Accepted: 06 November 2023;
Published: 17 November 2023.
Edited by:
Jose Renato Pinto, Florida State University, United StatesReviewed by:
Jennifer Stevenson, University of Kentucky, United StatesPaola Cecilia Rosas, University of Illinois Chicago, United States
Copyright © 2023 Pang, Zhang, Chen and Liu. 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: XiaoPing Chen, xpchen2009@163.com; WenMing Liu, tennisphd@163.com