Xiaojing Xie
Menghuan Li
Yue Zhang1
Xuejie Yi- 1 School of Sports and Health, Shenyang Sport University, Shenyang, China
- 2 School of Physical Education, Liaoning Normal University, Dalian, China
- 3 Sports and Health Research Center, Shenyang Sport University, Shenyang, China
The development, metabolism, and functional maintenance of skeletal muscle is a complex dynamic balance process. Its imbalance may lead to muscular dystrophy, muscle atrophy, and other diseases, which seriously affect human health. Therefore, in-depth exploration of the regulatory mechanisms governing skeletal muscle homeostasis and the identification of effective therapeutic targets have garnered significant attention. Recent studies reveal that the protein arginine methyltransferase CARM1 plays a central regulatory role in skeletal muscle biology. Substantial evidence indicates that abnormal CARM1 expression and activity disrupt muscle regeneration, metabolic balance, and stress responses, leading to muscle functional decline. This highlights its indispensable role in maintaining skeletal muscle homeostasis. Furthermore, exercise—an effective intervention for improving muscle quality and function—may exert its beneficial effects through mechanisms closely linked to CARM1 function. Therefore, this review systematically summarizes the roles of CARM1 in skeletal muscle development, regeneration, material metabolism, and homeostasis based on its molecular structure and fundamental functions. It further explores CARM1’s functional manifestations in muscle atrophy and exercise adaptation, providing a theoretical framework for comprehensively understanding its pivotal role in physiological adaptation and muscle diseases, while evaluating its potential value as a therapeutic target.
1 Introduction
Skeletal muscle accounts for approximately 40%–50% of body weight and serves as the core tissue sustaining locomotor function and metabolic homeostasis. Its progressive decline in mass and function represents a common pathological feature of aging and various chronic diseases, including muscular dystrophy, cancer cachexia, and diabetic myopathy, severely impairing patients’ quality of life and increasing mortality rates (Sartori et al., 2021). The maintenance of skeletal muscle homeostasis relies on the regenerative potential of muscle stem cells, the differentiation efficiency of myoblasts, and the precise balance of multiple physiological processes, including protein synthesis and degradation, energy metabolism, and oxidative stress. The destruction of this balance leads to muscle atrophy and regeneration disorder, which is the direct cause of the above diseases (Bonaldo and Sandri, 2013). Therefore, an in-depth analysis of its regulatory mechanisms holds significant value in both physiological and clinical applications.
With the rapid advancement of epigenetics research, the central role of post-translational modifications in determining cellular fate and regulating function has become increasingly prominent. Among these, protein arginine methylation, as a key epigenetic mechanism, dynamically and reversibly modifies numerous substrate proteins, extensively participating in processes such as gene transcription, signal transduction, and cellular stress responses (Blanc and Richard, 2017). Protein arginine methyltransferases (PRMTs) are the key enzymes that catalyze this modification. According to the different types of methylation, PRMTs can be divided into type I (catalytic asymmetric dimethylation, ADMA), type II (catalytic symmetric dimethylation, SDMA), and type III (catalytic monomethylation, MMA) (Tewary et al., 2019). In recent years, the roles of PRMTs in metabolic tissues and the regulation of cell fate have garnered significant attention. They precisely regulate cellular proliferation, differentiation, metabolism, and apoptosis by methylating histones, transcription factors, chromatin remodeling complexes, and signaling molecules.
Coactivator-Associated Arginine Methyltransferase 1 (CARM1), also known as PRMT4, is a member of this family. Transcriptome analysis revealed that the mRNA expression of CARM1 was significantly higher than that of other subtypes, such as PRMT1 to PRMT6, in mouse skeletal muscle and C2C12 myoblast model; This expression spectrum has been strictly confirmed in human quadriceps femoris. The transcript abundance of CARM1 is about 5 times higher than Protein Arginine Methyltransferase 1(PRMT1), Protein Arginine Methyltransferase 5(PRMT5), and Protein Arginine Methyltransferase 1(PRMT7), and 7-60 times higher than Protein Arginine Methyltransferase 2(PRMT2), Protein Arginine Methyltransferase 3(PRMT3), Protein Arginine Methyltransferase 6(PRMT6), and Protein Arginine Methyltransferase 9(PRMT9), occupying a dominant position (Wang et al., 2012; vanLieshout et al., 2019). This unique expression profile suggests CARM1 may play a critical role in skeletal muscle biology. CARM1 participates in key physiological processes such as cell fate determination, myofibrillar differentiation, and metabolic adaptation by catalyzing the arginine methylation of histones (e.g., Histone H3 Arginine 17, H3R17) and non-histone substrates (including various transcription regulators and signaling molecules) (Bauer et al., 2002; Jambhekar et al., 2019). Collectively, these findings demonstrate that CARM1-mediated protein methylation constitutes a pivotal hub linking epigenetic regulation to physiological and pathological states in skeletal muscle. However, current research remains fragmented, lacking systematic theoretical integration, which limits a comprehensive understanding of CARM1’s central role in skeletal muscle homeostasis.
Given that existing studies predominantly focus on isolated functional aspects of CARM1 and lack systematic integration within the context of skeletal muscle, this review aims to establish, for the first time, a multifunctional regulatory network of CARM1 in skeletal muscle. It delves into how CARM1 precisely regulates skeletal muscle life activities at both the epigenetic and signaling levels through its methyltransferase activity, with particular emphasis on its regulatory mechanisms in muscular diseases and sex differences. It further explores the potential therapeutic applications of targeting CARM1 for muscle-related disorders, aiming to provide a systematic theoretical foundation and research framework for deepening our understanding of skeletal muscle biology and developing novel therapeutic strategies.
2 Overview of CARM1
2.1 Structure of CARM1
Coactivator-associated Arginine Methyltransferase 1 (CARM1) belongs to the Type I PRMT family. Its name derives from its function as a nuclear receptor coactivator and its catalytic activity in asymmetric dimethylation of arginine residues (Chen et al., 1999). Molecularly, CARM1 comprises approximately 608 amino acids with a molecular weight of about 63 kDa (Berger et al., 2011). Its structure consists of three segments: a central catalytic core domain (residues 150-470 in mouse CARM1), flanked by an N-terminal domain (residues 1–130) and a C-terminal domain (residues 480–608) (Teyssier et al., 2002). The catalytic core domain exhibits high sequence conservation across all PRMT family members and is the key region for its methylation function. The N-terminal and C-terminal domains are also crucial for CARM1’s transcriptional co-activation function, regulating CARM1’s activity through interactions with other proteins and other mechanisms (Teyssier et al., 2002).
2.2 Fundamental molecular functions of CARM1
As a type I arginine methyltransferase, CARM1 primarily catalyzes asymmetric dimethylation at histone H3 position R17 (H3R17me2a) in skeletal muscle. During C2C12 cell differentiation, CARM1 modifies chromatin structure by transporting H3R17me2a—a critical histone mark—from the cytoplasm to the myonucleus, thereby driving muscle gene expression programs (Shen et al., 2018). Beyond histones, CARM1 recognizes multiple non-histone substrates, including the transcription coactivator E1A Binding Protein p300/CREB-Binding Protein(p300/CBP), the RNA-binding protein polyadenylate-binding protein 1 (PABP1), and human antigen R (HuR) (Li et al., 2002; Kaniskan et al., 2016). Among these, HuR, as a substrate, has been demonstrated to participate in regulating muscle differentiation processes, with its abnormalities linked to the pathogenesis of muscular dystrophy (Stone et al., 2021). The roles of other key substrates, such as the transcription coactivator p300/CBP and the RNA-binding protein PABP1, are primarily based on studies in non-muscle cell lines; their specific functions within skeletal muscle require further validation. In transcriptional regulation, CARM1 mainly acts as a coactivator, enhancing gene transcription activity by methylating the H3R17 site (Jacques et al., 2016). Simultaneously, it regulates the activity and stability of transcription factors such as p160 family coactivators, p53, and NF-κB, precisely controlling the expression programs of specific genes (Chen et al., 1999). This provides crucial assurance for the precise regulation of skeletal muscle gene expression.
CARM1’s enzymatic activity undergoes multi-level fine-tuning, with its C-terminal self-methylation modifying catalytic efficiency (Kuhn et al., 2011). This enzymatic activity is crucial for cellular development, as demonstrated in mice deficient in CARM1. These mice exhibit phenotypes similar to those of gene knockout models, including embryonic lethality, impaired T cell development, defective adipocyte differentiation, and reduced transcriptional coactivation activity, underscoring the irreplaceable nature of its catalytic function (Kim et al., 2010). Notably, phosphorylation at position S595 serves as a key molecular switch for CARM1’s response to oxidative stress signals. This phosphorylation modification triggers CARM1’s transport from the nucleus to the cytoplasm, enabling it to target cytoplasmic substrates (Cho and Kim, 2024a). This localization shift confers CARM1 a unique dual identity: as a nuclear transcription coactivator that regulates gene expression, and as a cytoplasmic stress-response enzyme that rapidly adjusts cellular homeostasis. This mechanism enables CARM1 to couple epigenetic programs with transient cellular metabolic states tightly. These discoveries establish the molecular basis for understanding its complex role in the specific tissue of skeletal muscle.
However, current research on the specific functions of CARM1’s functional domains within skeletal muscle remains limited. Studies in other cell types indicate that its catalytic and regulatory domains are crucial for enzymatic activity. Yet, whether these structure-function relationships exhibit specificity in the skeletal muscle context, and how muscle-specific binding partners influence its function, remain critical questions to be addressed. Collectively, these regulatory mechanisms ensure that CARM1 can respond to diverse physiological signals, exerting precise control over critical biological processes including skeletal muscle differentiation, metabolic regulation, and stress responses.
3 The role of CARM1 in muscle development
3.1 The role of CARM1 in regulating muscle stem cell activation and early differentiation
Satellite cells (i.e., muscle stem cells) reside beneath the basement membrane of muscle fibers and serve as the primary stem cells for skeletal muscle growth, repair, and regeneration (Mauro, 1961). They maintain low metabolic activity at rest but can rapidly activate, proliferate, and differentiate into mature muscle cells in response to stimuli such as muscle injury (Schultz et al., 1978; Bentzinger et al., 2012). The transcription factor Paired Box 7 (PAX7) serves as their specific marker and is crucial for maintaining stem cell properties and early differentiation. Mouse teratoma models demonstrate that PAX7 deficiency severely impairs myogenic differentiation, obstructing myofibrillar formation and maturation (Florkowska et al., 2020). Its downstream target, Myogenic Factor 5 (Myf5), plays a pivotal role in initiating differentiation, with its expression directly regulated by PAX7 (McKinnell et al., 2008). In goat models, Myf5 expression dynamics closely correlate with muscle maturation: it is broadly expressed early in development and progressively restricted to satellite cells and a few myonuclei as development progresses (Pani et al., 2025). PAX7 and Myf5 form a core axis regulating muscle stem cell fate, jointly governing maintenance and differentiation (Olguín and Pisconti, 2012). In late differentiation, Myogenic Enhancer Factor 2C (MEF2C) promotes the maturation of myogenic precursors into mature muscle fibers by activating muscle-specific genes (Piasecka et al., 2021).
Current research on CARM1 regulation mechanisms is primarily based on mouse and in vitro cell models. Kawabe et al. (Kawabe et al., 2012) demonstrated that CARM1 specifically methylates N-terminal arginine residues (positions 10, 13, 22, 37) of PAX7 during early differentiation, providing a binding site for the MLL1/2 complex. This recruits histone 3, lysine 4 (H3K4) methyltransferase to activate Myf5 transcription. This mechanism promotes the asymmetric division of satellite cells, balancing stem cell self-renewal (PAX7+/MYF5-) and differentiation initiation (PAX7+/MYF5+). In Duchenne muscular dystrophy (DMD) models, the inhibition of CARM1 activity reduces satellite cell asymmetric division and impairs muscle regenerative capacity (Chang et al., 2018). This pathological phenomenon, conversely, validates the critical role of the CARM1-PAX7-MYF5 regulatory axis in maintaining muscle stem cell pool homeostasis and governing initial differentiation. As differentiation progresses to later stages, CARM1’s regulatory focus shifts toward effectors like MEF2C. CARM1 directly interacts with the C-terminal region (amino acids 224–465) of MEF2C. In the presence of the SRC coactivator Glutamate Receptor Interacting Protein 1 (GRIP-1), CARM1 functions as a coactivator to enhance MEF2C’s transcriptional activation capacity, thereby activating muscle-specific gene expression and promoting myotube formation and terminal differentiation (Chen et al., 2002). This phased regulatory pattern, transitioning from early determinants to late effectors, enables CARM1 to precisely control the entire process of myogenic differentiation precisely, ensuring the smooth progression of muscle development and regeneration programs (Figure 1).
Figure 1. The role of CARM1 in muscle development. (a) During early muscle stem cell differentiation, CARM1 mediates specific methylation of the transcription factor PAX7. This modification creates binding sites for the MLL1/2 complex, activating Myf5 transcription activity to balance stem cell self-renewal (PAX7+/MYF5-) and differentiation initiation (PAX7+/MYF5+), thereby regulating the critical asymmetric division of satellite cells; (b) During mid-to-late differentiation, CARM1 synergizes with PRMT5 to methylate BRG1, facilitating SWI/SNF complex recruitment to promoter regions of muscle-specific genes (e.g., Ckm, Des). This modulates chromatin accessibility, establishing the foundation for gene expression; (c) As differentiation progresses to late stages, CARM1 methylates MEF2C to promote muscle stem cell terminal differentiation and fast-twitch fiber differentiation. CARM1 methylates HuR, affecting its stability and translation efficiency for multiple muscle differentiation-related mRNAs, thereby indirectly regulating myotube formation and maturation. Created in https://BioRender.com.
It is worth noting that direct validation studies using human primary muscle cells and clinical samples are currently lacking. Although cross-species comparisons indicate the conservation of relevant transcription factors, the specific regulatory mechanisms of CARM1 in human muscle stem cells require further experimental confirmation. This research gap limits our in-depth understanding of CARM1’s role in human muscle diseases.
3.2 Role of CARM1 in regulating myoblast differentiation and maturation
Following stem cell activation and transition to myoblasts, CARM1 continues to participate in regulating myoblast fusion and terminal differentiation into mature myotubes. This stage involves the temporal activation of multiple transcription factors and the precise regulation of muscle-specific gene expression networks.
CARM1 exhibits a temporally specific synergistic interaction pattern with another PRMT family member, PRMT5, during muscle differentiation (Nie et al., 2018). These two enzymes catalyze distinct types of arginine methylation modifications: PRMT5 primarily mediates symmetric dimethylation, while CARM1 predominantly catalyzes asymmetric dimethylation, each of which is associated with specific gene regulatory functions (Xu and Richard, 2021). During early muscle differentiation, PRMT5 is recruited to the promoter region of the myogenin gene. By modifying histone H4 arginine 3 (H4R3), it promotes the binding of the ATP-dependent chromatin remodeling enzyme Brahma-related gene 1 (BRG1), thereby restructuring chromatin and creating favorable conditions for the binding of myogenic transcription factors (Dacwag et al., 2007). As differentiation progresses into later stages, CARM1 assumes an increasingly critical role. CARM1 synergizes with PRMT5 to methylate specific arginine residues of BRG1, thereby promoting the recruitment of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex to the promoter regions of muscle-specific genes (Ckm and Des), further regulating chromatin accessibility (Dacwag et al., 2009) (Figure 1). Experimental evidence indicates that CARM1 deficiency significantly impairs this chromatin remodeling activity, leading to impaired expression of terminal differentiation genes, demonstrating that CARM1 is essential for chromatin remodeling of late differentiation genes (Dacwag et al., 2009).
Beyond regulating chromatin states via epigenetic mechanisms, CARM1 also participates in post-transcriptional regulatory networks of muscle differentiation by modifying RNA-binding proteins. CARM1 specifically methylates HuR, precisely regulating its binding capacity, subcellular localization, and functional activity (Ravel-Chapuis et al., 2022) (Figure 1). This modification directly impacts HuR’s stability and translational efficiency for various muscle differentiation-related mRNAs containing AU-rich elements, thereby establishing a fine-tuned post-transcriptional regulatory mechanism that indirectly influences myotube formation and maturation.
During muscle fiber maturation, CARM1 plays a further role in fiber type specialization and functional acquisition. In a zebrafish skeletal muscle development model, CARM1 promotes the differentiation of fast-twitch fibers explicitly and influences the spatial localization of slow-twitch fibers by regulating Myogenin expression (Batut et al., 2011). CARM1 deficiency causes impaired migration of slow-twitch fibers in zebrafish embryos, preventing them from reaching their correct anatomical positions. Mechanistic studies indicate that CARM1 establishes a molecular environment conducive to specific fiber type differentiation by maintaining the expression balance among key transcription factors such as Myogenin, Mef2C, and Myf5 (Batut et al., 2011). Further mouse studies revealed that CARM1 selectively promotes the differentiation of type II fast-twitch fibers with minimal impact on type I slow-twitch fibers (Wang et al., 2012) (Figure 1). However, these findings are primarily based on zebrafish and rodent models, and whether identical regulatory mechanisms exist in large mammals (e.g., sheep, horses, pigs) and humans remains unclear. Given significant differences in myofiber composition, metabolic characteristics, and functional requirements across species, direct extrapolation of these findings to human clinical applications warrants caution. Future research should prioritize functional validation of CARM1 in human skeletal muscle and clinically relevant large animal models.
Collectively, CARM1 constructs a continuous, multi-tiered regulatory network spanning from stem cell activation to myofibrillar maturation during muscle development. This network exhibits three key characteristics: temporal specificity (cooperation with PRMT5 at distinct developmental stages), multi-target regulation (controlling transcription factors, chromatin remodeling complexes, and RNA-binding proteins), and subtype selectivity (differentiated regulation of distinct myofibrillar types). Through these intricate regulatory mechanisms, CARM1 participates in all stages of muscle development, ensuring precise coordination of muscle tissue formation and fully demonstrating the central role of epigenetic regulation in tissue development.
4 CARM1 regulation of metabolic processes
4.1 Regulation of glucose metabolism
Glucose metabolism involves the absorption, storage, and breakdown of carbohydrates, achieving synthesis and degradation through a series of enzymatic reactions (Soo et al., 2023). In skeletal muscle, glucose metabolism not only supplies energy for muscle movement but also plays a crucial role in regulating insulin sensitivity, collectively supporting muscle health (Richter and Hargreaves, 2013). CARM1 exhibits a perplexing dual role in regulating glucose metabolism.
In tumor and non-muscle cell models, CARM1 typically functions as a direct modifier of metabolic enzymes, dynamically regulating enzyme activity through post-translational modifications, yet its effects demonstrate high heterogeneity. For instance, in tumor cells, CARM1 methylates Pyruvate Kinase M2 (PKM2). Methylated PKM2 interacts with endoplasmic reticulum calcium channels IP3Rs (IP3R1/3) and inhibits their expression, thereby reducing mitochondrial calcium uptake, decreasing oxidative phosphorylation, and promoting aerobic glycolysis (Liu et al., 2017). Conversely, in fibroblasts, CARM1-mediated methylation at PKM2-specific sites (R445/R447) promotes tetramer formation, significantly enhancing enzyme activity (Abeywardana et al., 2018). This tissue-specific regulation is further validated in other metabolic enzymes. Moreover, in hepatocellular carcinoma and osteoblasts, CARM1 induces complex metabolic reprogramming by methylating targets including Malate Dehydrogenase 1 (MDH1), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), and Protein Phosphatase 1 Catalytic Subunit Alpha (PPP1CA) (Zhong et al., 2018; Zhang et al., 2023). These studies indicate that in non-muscle tissues, CARM1 primarily intervenes in the allosteric regulation of metabolic enzymes through extensive and variable protein methylation modifications.
However, in skeletal muscle, CARM1 exhibits a distinctly high specificity. In skeletal muscle, CARM1 appears to function primarily as a transcriptional coactivator, exerting precise control over the transcriptional network regulating glycogen metabolism. Loss-of-function studies reveal that among over 200 metabolism-related genes, CARM1 deficiency specifically inhibits only core genes of the glycogen metabolic pathway—Glycogen Synthase 1 (Gys1), Phosphoglycerate Mutase 2 (Pgam2), and Muscle Glycogen Phosphorylase (Pygm), with no significant impact on genes involved in lipid oxidation or glucose homeostasis (Wang et al., 2012). This precise gene regulation function strictly depends on CARM1’s intrinsic enzymatic activity. This is demonstrated by the VLD mutant (SAM-binding domain mutation), which completely loses methylation activity and causes severe impairment of glycogen synthesis, while the E267Q mutant (catalytic site mutation), which partially retains activity, exhibits a dose-dependent intermediate phenotype (Wang et al., 2012). This finding reveals CARM1’s pivotal role as a central node in skeletal muscle glycogen homeostasis. Notably, the CARM1-regulated target gene network exhibits a high degree of overlap with human hereditary glycogen storage diseases (GSD). Loss-of-function mutations in GYS1, PGAM2, and PYGM genes are the direct causes of type 0 (Kollberg et al., 2007), X-linked (Zhang et al., 2022), and McArdle disease (Llavero et al., 2019)glycogen storage disorders, respectively. Furthermore, CARM1’s regulation of upstream signaling molecules, including AMPK (α2/γ3) and p38 Mitogen-Activated Protein Kinase (p38 MAPK), links its functional loss to pathological phenotypes such as Wolff-Parkinson-White syndrome (Wang et al., 2012). Thus, CARM1 in skeletal muscle is not merely a simple enzyme-modifying factor but regulates skeletal muscle glycogen metabolism by integrating transcriptional programs.
In summary, CARM1 exhibits complex and tissue-specific functions in regulating glycogen metabolism. Unlike its multifaceted, even contradictory “dual-sided” regulatory patterns in tumor and fibroblast cells, CARM1 exhibits high specificity in skeletal muscle, precisely focusing its function on glycogen metabolism pathways. This establishes CARM1’s physiological and clinical significance as a core master regulator of skeletal muscle glycogen homeostasis. In-depth analysis of these mechanisms not only helps elucidate tissue-specific gene regulation patterns but also provides new theoretical foundations and potential therapeutic targets for the treatment of metabolic diseases.
4.2 Regulation of protein metabolism
At the cellular level, skeletal muscle structure is primarily determined by the dynamic equilibrium between protein synthesis and degradation within myocytes (Yin et al., 2021). However, under certain pathological conditions, when the rate of protein degradation exceeds its synthesis rate, skeletal muscle mass and volume significantly decline—a phenomenon termed muscle atrophy (Fisher et al., 2017). Research indicates that skeletal muscle atrophy is primarily associated with abnormal activation of the ubiquitin-proteasome system, with CARM1 playing a crucial regulatory role in this process (Tintignac et al., 2015).
Muscle-specific E3 ubiquitin ligases Muscle Atrophy F-box (Atrogin-1) and Muscle-specific RING Finger Protein 1 (MuRF1) are essential components of this system. They specifically recognize and ubiquitinate myofibrils and muscle regulatory proteins, promoting their proteasomal degradation and thereby mediating muscle protein breakdown and myofibrillar atrophy (Pang et al., 2023). CARM1 influences muscle mass by regulating its expression levels. Under muscle atrophy conditions, CARM1 enhances the transcriptional activity of the core transcription factor Forkhead box O3 (FOXO3) by methylating specific arginine residues. In protein metabolism, this methylation primarily activates the ubiquitin-proteasome pathway (UPP), leading to upregulation of E3 ubiquitin ligases Atrogin-1 and MuRF1. This accelerates myosin degradation, thereby promoting muscle atrophy (Liu et al., 2019). Another crucial function of the CARM1-FOXO3 axis is regulating autophagy initiation, as detailed in Section 5.2 (Regulation of Autophagy in Skeletal Muscle). In muscle-specific CARM1 knockout (mKO) mice, muscle mass loss following sciatic nerve denervation was significantly reduced, accompanied by decreased expression of downstream atrophy genes MuRF1 and Atrogin-1, supporting CARM1 as a pro-atrophic factor under these conditions (Liu et al., 2019). However, a comprehensive analysis of multiple studies suggests that CARM1’s role in muscle atrophy may be condition-dependent. Following short-term pharmacological inhibition of CARM1 (e.g., using EZM2302), although its substrate methylation levels decreased, it failed to significantly mitigate the decline in muscle mass and muscle fiber cross-sectional area induced by neural disuse. It also did not reproduce the anti-atrophic effects observed in the aforementioned gene knockout model (Webb et al., 2023). This discrepancy suggests that CARM1 function may possess redundancy or alternative compensatory mechanisms under acute or short-term suppression conditions. More importantly, CARM1 gene and protein expression significantly increased in neurogenic disuse atrophy models, with sustained upregulation of intracellular localization and enhanced methylation activity. Conversely, in fasting-induced atrophy models, the methyltransferase activity of CARM1 decreased in both mice and humans, while protein levels remained unchanged—a stark contrast indicating potentially distinct regulatory mechanisms for CARM1 across different atrophy patterns (Stouth et al., 2024; Stouth et al., 2018). This condition-dependent expression pattern suggests CARM1 may exert both pathological pro-atrophic effects and adaptive protective functions under certain circumstances. However, existing evidence has significant limitations. Temporal experimental analyses are needed to clarify whether CARM1 upregulation is a driver or a consequence of muscle atrophy, and to reveal further whether it undergoes a dynamic transition between early protective and late pathological functions during disease progression.
Additionally, CARM1 plays a crucial role in nonsense-mediated mRNA decay (NMD) (Sanchez et al., 2016). When β-globin mRNA containing a premature termination codon (PTC) (MT) and normal mRNA (WT) were separately transfected into MN-1 control cells and CARM1-knockdown cells, results showed significantly reduced degradation of PTC-containing mRNA in CARM1-knockdown cells. This finding confirms that CARM1 promotes the degradation of mRNA containing premature termination codons (PTCs). Through this mechanism, CARM1 assists cells in efficiently recognizing and clearing abnormal mRNAs containing PTC, thereby preventing their translation into potentially harmful incomplete proteins (Sanchez et al., 2016). In spinal muscular atrophy (SMA) models, CARM1 protein levels are significantly elevated in spinal motor neurons and muscle tissues. This leads to an abnormally enhanced NMD process, affecting the maintenance of muscle function and repair-related genes: Growth Arrest and DNA Damage-inducible 45 alpha (Gadd45a), Activity-regulated Cytoskeleton-associated protein (Arc), and Asparagine Synthetase (Asns) mRNA, further exacerbating muscle atrophy (Sanchez et al., 2016).
In summary, CARM1 exhibits condition-dependent roles in protein metabolism regulation: under certain conditions (e.g., neurogenic disuse), it primarily promotes atrophy, while in other scenarios (e.g., fasting stress), it may exert adaptive regulatory functions. CARM1 participates in muscle mass regulation by activating the ubiquitin-proteasome system through FOXO3 methylation and promoting PTC degradation via nonsense-mediated mRNA decay (NMD). This complexity suggests that CARM1 may function both as a driver of atrophy and as a component of cellular stress responses. Its precise mechanisms of action and therapeutic target potential require further temporal and mechanistic studies to elucidate.
5 Role of CARM1 in regulating skeletal muscle homeostasis
5.1 Regulation of the oxidative stress response
Oxidative stress represents a pathological state characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense system within cells. As a high-oxygen-consuming tissue, skeletal muscle is particularly susceptible to oxidative stress due to its dense mitochondrial network (Chen et al., 2022). As the most significant metabolic organ in the human body, skeletal muscle requires precise regulatory mechanisms to maintain oxidative equilibrium (Lian et al., 2022). Oxidative stress forms a characteristic vicious cycle: excessive ROS damages mitochondrial DNA and the electron transport chain, while damaged mitochondria produce more ROS, further diminishing muscle fiber contractility (Wen et al., 2025). Concurrently, sustained oxidative stress activates cellular senescence programs, leading to myocyte growth arrest and reduced regenerative capacity, thereby accelerating muscle functional decline (Duranti, 2023).
CARM1, an epigenetic regulator, plays a role in oxidative stress responses, primarily through transcriptional regulation and post-translational protein modification. Under basal conditions, CARM1 is predominantly localized to the nucleus, precisely regulating key transcription factor networks to maintain mitochondrial homeostasis. Studies reveal that in CARM1 knockout (KO) mouse embryonic fibroblasts (MEFs), expression of key mitochondrial biosynthetic regulators Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-α) and Mitochondrial Transcription Factor A (TFAM) significantly increased, while expression of Dynamin-Related Protein 1 (DRP1), which regulates mitochondrial fission, decreased. This led to a morphology characterized by elongated, fused mitochondria. Reintroduction of wild-type CARM1 (WT) reverses this phenotype (Cho and Kim, 2024a). This demonstrates that CARM1 operates in the nucleus by inhibiting PGC-1α and TFAM expression to limit mitochondrial biogenesis, while simultaneously promoting DRP1 expression to regulate mitochondrial fission. This bidirectional regulatory mechanism plays a crucial role in maintaining the balance between mitochondrial number and function (Figure 2).
Figure 2. Molecular mechanism of CARM1 regulating mitochondrial dynamic balance in different cellular states. (a) In the normal physiological state, CARM1 plays a role in regulating mitochondrial biogenesis and fission. Through methylating H3R17, on one hand, CARM1 suppresses mitochondrial biogenesis by inhibiting the mRNA and protein levels of PGC-1α and TFAM. On the other hand, it enhances the expression of DRP1 protein to modulate mitochondrial fission, thereby preserving mitochondrial homeostasis. (b) Under oxidative stress conditions, CARM1 induces mitochondrial dysfunction. Under oxidative stress conditions, elevated ROS levels activate p38γ MAPK, resulting in the phosphorylation of CARM1 at the S595 site. This phenomenon promotes the translocation of CARM1 from the nucleus to the cytoplasm, where it directly methylates DRP1 to accelerate mitochondrial fission and form a positive feedback loop. Arrows indicate promotional effects, and T-shaped lines indicate inhibitory effects. Me: methylation; P: phosphorylation. Created in https://BioRender.com.
More critically, CARM1 responds to oxidative stress signals by undergoing subcellular localization shifts, thereby establishing a precise positive feedback regulatory loop. Studies show that under oxidative stress conditions induced by Hydrogen Peroxide (H2O2) or Lipopolysaccharide (LPS), CARM1 translocates from the nucleus to the cytoplasm in 10T1/2 cells (a mouse embryonic fibroblast cell line). A process blocked by the p38 MAPK inhibitor (BIRB 796) or nuclear export inhibitor (EZM2302), indicating dependence on p38γ MAPK activation and CRM1-mediated nuclear export mechanisms (Cho and Kim, 2024a; Cho and Kim, 2024b). Mechanistically, oxidative stress elevates intracellular reactive oxygen species (ROS) levels, activating p38γ MAPK, which phosphorylates CARM1 at the S595 site and promotes its cytoplasmic translocation (Cho and Kim, 2024a). In the cytoplasm, CARM1 directly methylates and activates DRP1, thereby enhancing mitochondrial fission and promoting further ROS production, which accelerates cellular senescence (Cho and Kim, 2024a; Cho and Kim, 2024b). Under oxidative stress, CARM1 knockout MEF cells exhibited significantly elevated mitochondrial membrane potential (MMP) and oxygen consumption rate (OCR), with mitochondria adopting a more elongated and fused morphology; In contrast, CARM1-WT MEF cells under identical conditions exhibited markedly decreased MMP and OCR, further confirming CARM1’s negative regulatory role in mitochondrial function (Cho and Kim, 2024b). This positive feedback loop mechanism—“ROS-p38γ-CARM1-DRP1-more ROS”—is particularly pronounced under physiological and pathological conditions such as intense exercise or aging. It rapidly amplifies initial oxidative stress signals, triggering adaptive or pathological cellular responses (Figure 2).
It is worth noting that the molecular details of the aforementioned feedback circuit are primarily based on data from fibroblasts. Although this intricate molecular chain has not been fully replicated in skeletal muscle in vivo, multiple lines of evidence strongly suggest its existence and functional relevance. In skeletal muscle undergoing chronic oxidative stress associated with aging, disuse, or neuromuscular diseases, persistent activation of the p38 MAPK pathway, elevated DRP1 activity, mitochondrial fragmentation, and substantial ROS accumulation have been observed (Odeh et al., 2020; Favaro et al., 2019). These in vivo pathological phenotypes closely align with the aforementioned cellular pathways, suggesting that the CARM1-mediated pathway may serve as a critical bridge linking oxidative stress to skeletal muscle mitochondrial dysfunction.
In summary, CARM1’s significance lies in its role as a molecular hub integrating nuclear transcriptional programs with cytoplasmic rapid stress responses. The “ROS–p38γ–CARM1–DRP1-more ROS” pathway elucidated in fibroblasts provides a compelling candidate model for understanding the amplification mechanisms of oxidative stress in skeletal muscle. Validating this cellular model within skeletal muscle and exploring its muscle-specific regulatory mechanisms represent future research directions. This holds significant theoretical value and may also provide novel potential targets for developing targeted strategies against muscle atrophy and degenerative diseases.
5.2 Regulation of Autophagy in Skeletal Muscle
Autophagy is a highly conserved intracellular degradation and recycling mechanism that selectively degrades damaged organelles, misfolded protein aggregates, and other cellular components via the lysosomal system, playing a central role in maintaining intracellular homeostasis (Levine and Kroemer, 2019). In skeletal muscle, precise regulation of autophagic flux is crucial for maintaining myofibrillar quality, repairing injuries, and balancing energy metabolism (Singh et al., 2022). CARM1 establishes a sophisticated multi-tiered regulatory network through arginine methylation, coordinating three key pathways to maintain muscle autophagy homeostasis jointly.
During the early stages of autophagy initiation, CARM1 controls the activation of AMP-activated protein kinase (AMPK), the central energy sensor, through epigenetic mechanisms. AMPK serves as a core regulator of cellular energy metabolism, activating autophagy in response to energy stress to maintain energy balance (Feng et al., 2024). Stouth et al. (Stouth et al., 2020)revealed that CARM1-mediated methylation is a prerequisite for AMPK activation. Under neurogenic muscular atrophy and energy stress conditions, the interaction between CARM1 and AMPK significantly intensifies, catalyzing ADMA methylation at the 5th position of AMPK. This methylation event is crucial as it provides the molecular basis for AMPK Thr172 phosphorylation and subsequent kinase activation. Mechanistic studies indicate that CARM1-activated AMPK precisely initiates autophagy through a dual mechanism: on one hand, AMPK directly phosphorylates the Ser555 activation site of Unc-51-like autophagy activating kinase 1 (ULK1); Second, it suppresses Mechanistic Target of Rapamycin (mTOR) complex activity, thereby releasing mTOR’s inhibitory phosphorylation of ULK1 Ser757 (Stouth et al., 2020; Park et al., 2023). However, in skeletal muscle-specific CARM1 knockout (mKO) mice, impaired AMPK methylation prevents its phosphorylation-mediated activation, triggering a cascade of events: Ser555 phosphorylation of ULK1 fails to increase under stress conditions, and mTOR inhibition of Ser757 cannot be relieved, resulting in complete disruption of the autophagy initiation signal (Stouth et al., 2020). Fasting experiments further confirmed that CARM1 deficiency reduces the conversion of lipidated LC3 (LC3-II) and impairs autophagy flux (Stouth et al., 2024). This indicates CARM1 is a critical component in skeletal muscle’s response to energy stress and initiation of the autophagy program.
Following rapid initiation, CARM1 further maintains and amplifies autophagy efficacy by co-activating the FOXO3 transcription factor. Unlike the acute stress response mediated by AMPK, FOXO3 primarily governs the transcriptional expression of autophagy-related genes (ATGs) (Mammucari et al., 2007). CARM1 significantly enhances FOXO3’s nuclear transcriptional activity through asymmetric dimethylation (ADMA) modification, specifically upregulating autophagy-initiating factors Autophagy-related protein 13 (Atg13) and Autophagy-related protein 14 (Atg14), thereby promoting sustained autophagosome formation (Liu et al., 2019). Notably, this mechanism aligns with CARM1’s regulation of the ubiquitin-proteasome system (see Section 4.2), which jointly drives muscle atrophy. Functional validation revealed the critical physiological significance of this regulation: In both neurotomy and dexamethasone-induced muscle atrophy models, CARM1 knockdown or inhibition significantly slowed atrophy progression, manifested as increased wet weight of the tibialis anterior muscle, markedly improved muscle fiber cross-sectional area, reduced methylation levels of FoxO3, and decreased LC3-II/LC3-I ratio—a marker of autophagy (Liu et al., 2019). This finding not only elucidates the molecular mechanism by which CARM1 coordinates autophagy and protein degradation at the transcriptional level but also suggests its potential as a therapeutic target for muscle atrophy.
As the final line of defense in quality control, mitochondria are crucial for maintaining muscle energy homeostasis, and their dysfunction is a core feature of muscle aging and disease (Fealy et al., 2021). CARM1 resides upstream of the classical PTEN-induced putative kinase 1-Parkin (PINK1-Parkin) pathway. It enhances the ubiquitinating activity of the E3 ubiquitin ligase Parkin by directly methylating it, ensuring damaged mitochondria are promptly tagged and cleared. Under fasting conditions, CARM1 deficiency disrupts Parkin-mediated clearance mechanisms, resulting in the abnormal accumulation of dysfunctional mitochondria and a decrease in oxidative phosphorylation complex activity (Stouth et al., 2024). Clinical sample analysis reveals that the dynamic changes in CARM1 activity in human muscle during fasting highly correlate with mouse models (Stouth et al., 2024). This suggests that CARM1 functions as a crucial epigenetic regulator, coordinating mitochondrial quality control under nutritional stress.
In summary, CARM1 establishes a multi-tiered autophagy regulatory network in skeletal muscle by synergistically modulating three key pathways: the AMPK-mTOR signaling pathway, FOXO3-mediated autophagy gene transcription, and Parkin-dependent mitophagy. This suggests that dysregulated CARM1 expression correlates with muscle diseases, and targeting CARM1 may offer a novel therapeutic strategy for muscle atrophy. However, how CARM1 dynamically balances pathway activities under different physiological states and whether tissue-specific co-regulators exist to recognize potential tissue-specific co-factors remain challenges for future research.
6 CARM1 and exercise
Skeletal muscle serves as the core motor organ of the human body, with its intricate functions and adaptability forming the cornerstone for maintaining health and optimizing athletic performance (Lim et al., 2022). Exercise stimuli induce a series of complex physiological and molecular changes in skeletal muscle, including myofibrillar type switching, mitochondrial proliferation, and metabolic reprogramming (Spaulding and Selsby, 2018). CARM1 plays a pivotal role in this process, with its expression and activity precisely regulated by exercise timing. Transcriptomic and proteomic analyses have confirmed CARM1 as one of the most highly expressed members of the PRMT family in human quadriceps femoris muscle, suggesting its critical hub status in skeletal muscle physiological regulation (vanLieshout et al., 2019).
Exercise stimulation induces time-dependent changes in CARM1 expression and activity. During the acute exercise response phase (90-min treadmill running), H3R17 methylation status significantly increased in mouse gastrocnemius myonuclei, accompanied by elevated CARM1 methyltransferase activity in the myonucleolar compartment (Vanlieshout et al., 2018). This suggests CARM1-mediated histone methylation serves as an early initiation signal for skeletal muscle adaptive remodeling. In a chronic exercise adaptation model, skeletal muscle-specific CARM1 knockout (mKO) mice exhibited significantly reduced exercise endurance and reduced mitochondrial volume after 8 weeks of voluntary wheel running, consistent with findings of sustained CARM1 protein upregulation in humans following 2 weeks of Sprint Interval Training (SIT) (vanLieshout et al., 2019; Vanlieshout et al., 2024). This confirms the species conservation of CARM1 expression changes during exercise adaptation, where it mediates the link between the exercise stimulus and skeletal muscle adaptive remodeling through regulation of expression and subcellular relocalization.
CARM1 exhibits sex-specific regulation during skeletal muscle exercise, with effects that depend on the exercise pattern. In a single acute running test, male skeletal muscle-specific CARM1 knockout (mKO) mice showed impaired exercise endurance accompanied by reduced expression of the key metabolic regulator PGC-1α (vanLieshout et al., 2022). However, in an 8-week chronic voluntary wheel-running experiment, female CARM1 mKO mice exhibited a sharp decline of approximately 70% in daily running distance, whereas male mKO mice showed no significant difference (Vanlieshout et al., 2024). This result eliminated the commonly observed female exercise advantage, aligning the exercise capacity of male and female mKO mice. This sex difference suggests CARM1 may play a critical role in exercise motivation or fatigue tolerance in female mice, potentially through estrogen signaling pathways. The exercise endurance advantage in females is partially dependent on estrogen regulation, which modulates skeletal muscle function through receptors such as ERα and ERRα (Oydanich et al., 2019; Yoh et al., 2023). As a coactivator of ER-mediated transcription, CARM1 promotes the expression of estrogen-responsive genes by methylating histones H3 at Arg17 and Arg26 sites or directly methylating ERα and its cofactors (Habashy et al., 2013; Peng et al., 2020). Consequently, its absence may disrupt this signaling pathway and impair exercise performance. However, despite histological analyses supporting these associations, in vivo evidence remains lacking for direct binding or methylation modifications between CARM1 and ER or its downstream nuclear receptors (e.g., ERRα) within skeletal muscle cell nuclei via ChIP/Co-IP assays. Consequently, future studies should focus on elucidating how CARM1 specifically influences metabolic reprogramming in female muscle. Additionally, we found that basal CARM1 expression levels in female muscle tissue are on average 25% lower than in males (Webb et al., 2023). This lower baseline expression may amplify the relative loss of activity caused by CARM1 deficiency, increasing female muscle dependence on estrogen-CARM1-mediated expression of energy metabolism genes like PGC-1α and AMPK. This explains the more severe decline in endurance observed in female mKO mice (Park et al., 2023; Yadav et al., 2003).
The mechanism of CARM1 action in skeletal muscle is highly complex and involves synergistic interactions within the PRMT family. In the absence of CARM1, PRMT7)expression is significantly upregulated, potentially serving as a compensatory mechanism to maintain skeletal muscle function (Wei et al., 2021; vanLieshout and Ljubicic, 2019). Concurrently, PRMT1 and PRMT5 also participate in metabolic regulation, forming a functionally complementary network with CARM1 (vanLieshout and Ljubicic, 2019).
In summary, CARM1 plays a crucial role in skeletal muscle exercise adaptation, with its function being comprehensively regulated by exercise patterns, muscle type, and sex differences. These findings not only provide a novel epigenetic perspective for understanding sex differences in skeletal muscle exercise-induced remodeling but also emphasize the importance of fully considering muscle type specificity and sex factors in future research. Future studies should prioritize validating the direct interaction between CARM1 and the estrogen receptor using techniques such as ChIP/Co-IP, thereby providing a more robust molecular foundation for developing gender-specific exercise intervention strategies.
7 Discussion
This review systematically outlines the pivotal regulatory role of CARM1 as a spermidyl methyltransferase in skeletal muscle physiology. CARM1 exhibits multi-level, multi-stage regulatory functions in skeletal muscle development, metabolism, and the maintenance of homeostasis. From the activation of muscle stem cells and their asymmetric division, to myoblast differentiation and myofibrillar type specialization, and further to metabolic regulation and stress responses, CARM1 precisely modulates key transcription factors, chromatin remodeling complexes, metabolic enzymes, and autophagy-related proteins through its methyltransferase activity, thereby constructing a complex regulatory network. In metabolism, CARM1 specifically regulates the expression of key genes involved in glycogen metabolism, with its dysregulation linked to glycogen storage diseases. In protein metabolism, CARM1 plays a role in the onset and progression of muscle atrophy by regulating the ubiquitin-proteasome system and nonsense-mediated mRNA decay. In regulating oxidative stress and autophagy, CARM1 influences mitochondrial function and autophagy flux through the “ROS–p38γ–CARM1–DRP1” positive feedback loop and multiple pathways, including the AMPK-mTOR, FOXO3, and Parkin pathways, thereby regulating muscle homeostasis and aging processes. Furthermore, CARM1 exhibits time- and sex-dependent regulation during exercise adaptation, with its expression and activity modulated by exercise pattern, intensity, and sex, suggesting its essential and complex role in exercise physiology and metabolic health.
Despite these advances, several key challenges remain in understanding CARM1’s role in skeletal muscle physiology and pathology: (1) The precise mechanism underlying CARM1 substrate specificity remains incompletely elucidated, particularly how it selectively targets different substrates under varying physiological conditions; (2) The spatiotemporal specificity of CARM1 regulatory networks and their differential actions across distinct muscle fiber types require further investigation; (3) How CARM1-mediated epigenetic memory influences long-term skeletal muscle adaptation and disease progression remains unclear. Future research should focus on the following directions: First, apply single-cell epigenomics technologies to decipher the precise role of CARM1 in muscle stem cell fate determination; second, develop CARM1 substrate-specific inhibitors to explore their potential for targeted intervention in diseases such as muscular atrophy and diabetic myopathy; Third, integrating a gender medicine perspective to investigate the differential mechanisms of CARM1-mediated epigenetic regulation in skeletal muscle adaptation across genders. Finally, establishing an integrated bioinformatics platform to construct a multi-level regulatory network model of CARM1 in skeletal muscle.
In summary, as a pivotal hub linking epigenetic modifications to skeletal muscle function, CARM1 not only offers new insights into muscle physiology and pathology but also provides potential targets for developing personalized, precision intervention strategies for skeletal muscle disorders. As research progresses, the full landscape of CARM1’s regulatory network will gradually emerge, paving new pathways for maintaining skeletal muscle function and intervening in related diseases.
Author contributions
XX: Writing – original draft, Writing – review and editing. ML: Writing – review and editing. YZ: Writing – review and editing. ZB: Writing – review and editing. XY: Funding acquisition, Supervision, Writing – review and editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was funded by the Basic Research Project of Liaoning Provincial Universities (Grant No. LJKMZ20221616).
Acknowledgements
The authors wish to express their gratitude to all who have made valuable contributions to this review. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Correction note
This article has been corrected with minor changes. These changes do not impact the scientific content of the article.
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Keywords: autophagy, CARM1, exercise, metabolism, muscle atrophy, muscle development, oxidative stress, skeletal muscle
Citation: Xie X, Li M, Zhang Y, Bao Z and Yi X (2025) Recent advances in the role of CARM1 in skeletal muscle development, metabolism, and homeostasis maintenance. Front. Cell Dev. Biol. 13:1709515. doi: 10.3389/fcell.2025.1709515
Received: 20 September 2025; Accepted: 09 December 2025;
Published: 19 December 2025; Corrected: 20 January 2026.
Edited by:
Federica Cirillo, IRCCS San Donato Polyclinic, ItalyReviewed by:
Naresh Chandra Bal, KIIT University, IndiaVladimir Ljubicic, McMaster University, Canada
Copyright © 2025 Xie, Li, Zhang, Bao and Yi. 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: Xuejie Yi, eWl4dWVqaWU4Mzg3QDE2My5jb20=