Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function

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IntroductionAs life expectancy continues to increase, preservation of functional independence and physiological resilience, rather than lifespan alone, has emerged as a central biomedical objective. Skeletal muscle is a major determinant of healthspan, governing locomotion, metabolic homeostasis and systemic stress tolerance1,2. Age-associated deterioration of muscle mass, strength and contractile performance culminates in sarcopenia, a condition strongly associated with frailty, falls, insulin resistance and increased mortality3. While reduced physical activity, endocrine alterations and nutritional insufficiency contribute to sarcopenia, these factors do not fully account for the early and progressive decline in muscle function observed with ageing4,5.Accumulating evidence identifies mitochondrial and metabolic dysfunction as central drivers of sarcopenia and neuromuscular decline6,7. Ageing muscle exhibits reduced oxidative phosphorylation efficiency, impaired redox balance and defective mitochondrial quality control, abnormalities that precede overt muscle loss and correlate more strongly with weakness and fatigability than muscle mass itself8,9,10. Importantly, mitochondrial dysfunction extends beyond myofibres to motor neurons and neuromuscular junctions (NMJs), implicating coordinated failure of neuromuscular bioenergetics in functional decline11,12,13.Mitochondrial stress responses are tightly coupled to metabolic signalling pathways that sense energetic and nutrient status, particularly AMP-activated protein kinase (AMPK), Forkhead box O (FOXO) transcription factors and mechanistic target of rapamycin (mTOR)14,15. This signalling triad governs mitochondrial biogenesis, autophagy and mitophagy, proteostasis, and anabolic restraint16,17,18. Dysregulation of these pathways shifts mitochondrial stress responses from adaptive remodelling toward bioenergetic failure and degeneration.Within this regulatory landscape, protein arginine methyltransferases (PRMTs) have emerged as critical modulators of metabolic and stress signalling. PRMTs catalyse arginine methylation of histone and non-histone substrates, thereby regulating protein–protein interactions, subcellular localization, stability and transcriptional output19,20. Although historically studied as epigenetic regulators, PRMTs are now recognized as broad signalling integrators that modify transcriptional coactivators, transcription factors, kinases, RNA-binding proteins and stress-response machinery21,22,23.Importantly, PRMTs do not function as primary metabolic sensors. Instead, they tune the amplitude, duration and context of canonical stress pathways, including AMPK, FOXO and mTOR signalling24,25,26,27,28. Through this modulatory role, PRMTs act as molecular rheostats that determine whether mitochondrial and metabolic stress elicits adaptive renewal, such as mitochondrial biogenesis and selective autophagy, or progresses toward maladaptive outcomes, including oxidative damage, excessive catabolism, NMJ instability and neuromuscular degeneration. In this Review, we incorporate current evidence to propose that dysregulation of PRMT-regulated metabolic stress signalling represents a key upstream mechanism driving mitochondrial dysfunction, sarcopenic progression and loss of neuromuscular healthspan.Mitochondrial dysfunction as a central driver of muscle ageing and neuromuscular degenerationMitochondria serve as the primary metabolic hubs of skeletal muscle, integrating ATP production, substrate utilization, redox signalling and adaptive stress responses3,29. With ageing, muscle mitochondria exhibit reduced respiratory efficiency, altered fission–fusion balance, impaired mitochondrial turnover, and accumulation of mitochondrial DNA and protein damage30,31. These defects compromise energy supply whilst increasing reactive oxygen species (ROS) production, directly linking bioenergetic insufficiency to oxidative stress.Crucially, mitochondrial dysfunction is not merely a consequence of muscle loss but also an early and causative event in neuromuscular ageing6,32. Declines in mitochondrial respiratory capacity and coupling efficiency correlate more closely with muscle weakness and fatigability than with muscle mass alone8,33. This indicates that age-related declines in muscle strength and contractile performance can occur independently of muscle size, a phenomenon referred to as dynapenia, which is distinct from sarcopenia and is closely linked to mitochondrial dysfunction34,35. Excess mitochondrial ROS damages contractile proteins, calcium-handling machinery and signalling components, reinforcing a feed-forward cycle of functional decline36. Consistent with this, skeletal muscle-specific deletion of MnSOD (SOD2) increases mitochondrial ROS, impairing contractile force, endurance and calcium handling, and causing NMJ fragmentation, all without reducing muscle mass37.Mitochondrial impairment also disrupts intracellular signalling pathways governing proteostasis, inflammation and regeneration38,39,40. Defective autophagy and mitophagy permit accumulation of dysfunctional organelles, overwhelming protein quality control systems and destabilizing myofibre architecture11,41,42,43,44,45. These changes sensitize muscle to FOXO-driven catabolic signalling and limit adaptive remodelling under stress.Importantly, mitochondrial dysfunction in muscle not only affects the muscle itself but also extends to the NMJ and motor neurons. Crucially, these effects are not restricted to motor neuron, Schwann cell-specific mitochondrial dysfunction models, and muscle-specific mitochondrial defect models provide compelling evidence that primary mitochondrial dysfunction in muscle is sufficient to destabilize the NMJ and induce secondary neuronal pathology, underscoring the bidirectional nature of neuromuscular degeneration (Table 1). Skeletal muscle mitochondria form a specialized network with spatially distinct subpopulations: subsarcolemmal mitochondria beneath the plasma membrane contribute to local ATP supply and participate in Ca²⁺, insulin, and IGF signalling and ROS sensing, whereas intermyofibrillar mitochondria primarily support ATP production for muscle contraction through oxidative phosphorylation46. Of note, mitochondria positioned beneath the NMJ (subsynaptic mitochondria) represent a specialized subsarcolemmal mitochondrial subpopulation, exhibiting the highest mitochondrial density within the fibre to meet the substantial energy demands of acetylcholine signalling and ion pump activity, and are particularly vulnerable due to their high local ATP demand and strict redox requirements47,48. Local mitochondrial failure compromises synaptic maintenance and transmission, reducing the reliability of neuromuscular transmission and predisposing NMJs to fragmentation and denervation. Reduced neuromuscular activity further exacerbates mitochondrial stress within muscle fibres12,49,50, establishing a bidirectional mitochondria–neuromuscular axis in which metabolic failure and neuromuscular instability amplify one another during ageing (Fig. 1).Fig. 1: The metabolic–mitochondrial–neuromuscular axis exacerbates muscle degeneration.Full size imageThe neuromuscular system is an integrated network comprising the brain, spinal cord, motor neurons, neuromuscular junctions and skeletal muscle, in which muscle actively communicates with the nervous system rather than serving as a passive target. Systemic homeostasis depends on sustained cellular energy supply and effective oxidative stress control, both of which rely on intact metabolic function and mitochondrial integrity. Nutritional imbalance, physical inactivity and chronic inflammation disrupt metabolic homeostasis, leading to lipid accumulation, impaired glucose metabolism, reduced protein synthesis and decreased availability of branched-chain amino acids (BCAAs). These metabolic disturbances compromise mitochondrial quality control, resulting in reduced ATP production and excessive reactive oxygen species (ROS) generation. The ensuing bioenergetic failure and oxidative stress destabilize muscle structure and neuromuscular signalling. Neuromuscular junctions, which are highly enriched in mitochondria, are particularly vulnerable to defects in mitochondrial quality control, with dysfunction propagating between muscle fibres and motor neurons. This pathological cascade accelerates degenerative muscle disorders, including motor neuron diseases, myopathies, vulnerability, disease severity and patient mortality. UPR, unfolded protein response. This figure was generated using Biorender.com.Table 1 Phenotypes and mechanisms of tissue-specific mitochondrial defect models in myofibres, motor neurons and Schwann cells.Full size tablePRMT-dependent regulation of mitochondrial plasticity and metabolic stress signallingPRMTs as integrators of mitochondrial quality control and metabolic signallingMitochondrial homeostasis is maintained through coordinated regulation of mitochondrial biogenesis, dynamics (fusion and fission), unfolded protein response (UPRmt) and selective turnover (mitophagy), which together determine mitochondrial quality rather than abundance alone51,52. These processes are tightly integrated with metabolic signalling through the AMPK–FOXO–mTOR axis, which senses energetic stress, oxidative damage and nutrient availability to balance renewal, degradation, and growth13,14,15. Low-energy states activate AMPK–FOXO-driven catabolic programmes, whereas nutrient sufficiency engages mTOR-dependent anabolic signalling, with both arms directly modulating mitochondrial quality control14,15 (Fig. 2).Fig. 2: Metabolic stress-responsive mTOR–AMPK–FOXO axis in mitochondrial quality control.Full size imageNutrient and energy status regulate the mechanistic target of rapamycin (mTOR)–AMP-activated protein kinase (AMPK)–Forkhead box O (FOXO) axis, with low energy activating AMP–FOXO-driven catabolic signalling and nutrient sufficiency engaging mTOR-dependent anabolic programmes, together coordinating mitochondrial quality control. AMPK phosphorylates PGC1α to enhance its transcriptional activity and induce downstream TFAM, while FOXO further promotes PGC1α expression. In contrast, mTOR phosphorylates 4EBP1 to stimulate translation of mitochondria-associated proteins. Mitophagy is promoted by AMPK and FOXO but suppressed by mTOR. AMPK phosphorylates ULK1 at Ser317 and Ser777 to initiate autophagy, whereas mTORC1 phosphorylates ULK1 at Ser757, preventing AMPK interaction and inhibiting autophagy initiation. Mitochondrial dynamics are context-dependent: mTOR can promote fusion via MFN2 or, under stress, drive fission through MTFP-mediated DRP1 activation; AMPK similarly promotes fission via DRP1, while FOXO may influence fission indirectly. Mitochondrial unfolded protein response (UPRmt) signalling is mediated by ATF4, with mTOR enhancing ATF4 activity via phosphorylation, AMPK increasing ATF4 translation, and FOXO interacting with ATF4 to further amplify its transcriptional activity. This figure was generated using Biorender.com.PGC1α, a master regulator of mitochondrial biogenesis, is phosphorylated by AMPK, enhancing its transcriptional activity53,54,55. AMPK also activates FOXO, which further induces PGC1α expression through direct binding or promoter engagement, leading to downstream induction of TFAM and mitochondrial gene transcription56,57,58. In contrast, mTOR promotes mitochondrial biogenesis by phosphorylating 4EBP1, releasing eIF4E and enhancing translation of mitochondria-related proteins59.Mitophagy is primarily stimulated by AMPK and FOXO, whereas mTOR acts as a negative regulator. AMPK phosphorylates ULK1 at Ser317 and Ser777, initiating LC3-dependent autophagosome formation and mitophagy60. Conversely, mTORC1 phosphorylates ULK1 at Ser757, preventing its interaction with AMPK and suppressing autophagy initiation61. FOXO transcription factors upregulate core autophagy genes and selectively induce mitophagy-specific genes, including PINK1, Parkin and BNIP3 (refs. 62,63,64).Mitochondrial dynamics regulated by mTOR, AMPK and FOXO are highly context-dependent. mTOR can promote mitochondrial fusion via MFN2 activation but, under stress conditions such as amyloid-β exposure, it enhances MTFP1 translation, driving DRP1 phosphorylation and fission. AMPK similarly promotes fission through DRP1 activation65,66,67,68. Although FOXO factors do not directly control fusion–fission gene expression, FOXO1 inhibition correlates with decreased DRP1 expression and Ser616 phosphorylation, suggesting an indirect regulatory role69.UPRmt signalling is largely mediated by ATF4. mTOR directly phosphorylates ATF4 to promote expression of UPRmt genes70, while AMPK activation enhances ATF4 translation without direct phosphorylation71. FOXO transcription factors interact with ATF4 to amplify its transcriptional activity, though direct FOXO-dependent activation of UPRmt genes remains unclear72. PRMT-dependent arginine methylation intersects this network, coordinating mitochondrial plasticity with metabolic state rather than acting on isolated quality-control pathways (Fig. 3).Fig. 3: Differential roles of PRMT isoforms in mitochondrial homeostasis.Full size imageProtein arginine methyltransferase (PRMT) family members act as key regulators linking mitochondrial homeostasis to cellular stress responses through isoform-specific mechanisms. Metabolic dysfunction driven by lipid accumulation, chronic inflammation and dysregulated signalling imposes cellular stress that disrupts mitochondrial function in the neuromuscular system. PRMT enzymes mitigate these defects by regulating mitochondrial quality control at both epigenetic and non-epigenetic levels. PRMT1 and PRMT7 enhance PGC1α expression to promote mitochondrial biogenesis, whereas CARM1 has been reported to suppress biogenesis. Mitophagy is primarily regulated by PRMT1 and CARM1, with CARM1 additionally promoting DRP1 expression and activation under oxidative stress. In the context of mitochondrial unfolded protein response (UPRmt), PRMT1 and PRMT5 suppress ATF4 expression and transcriptional activity, while PRMT7 enhances HSP70 activity, indicating isoform-specific roles of PRMTs in coordinating mitochondrial stress responses. This figure was generated using Biorender.com.Collectively, AMPK promotes mitochondrial biogenesis and initiates autophagy and mitophagy, FOXO coordinates stress-adaptive catabolic programmes, and mTOR integrates nutrient cues to drive anabolic growth while restraining autophagic flux16,17,18. PRMTs fine-tune these pathways by modulating transcriptional output, signalling intensity and pathway crosstalk.To date, nine PRMT isoforms (PRMT1–9) have been identified in mammals, and they are broadly classified into three types based on the methylarginine products they generate (Table 2). Type I PRMTs, including PRMT1, PRMT2, PRMT3, CARM1 (PRMT4), PRMT6 and PRMT8, catalyse the formation of asymmetric dimethylarginine (ADMA). Type II PRMTs, represented by PRMT5 and PRMT9, generate symmetric dimethylarginine (SDMA). Type III PRMTs, with PRMT7 as the only known member, produce monomethylarginine. These distinct forms of arginine methylation differentially regulate protein function and gene expression, thereby playing critical roles in cellular stress responses.Table 2 Overview of PRMT family members, including key substrates, tissue specificity and functional outcomes.Full size tableIn this section, we first outline core mitochondrial quality control pathways, followed by PRMT-specific regulatory roles (PRMT1, CARM1, PRMT5, PRMT7 and PRMT8), with particular emphasis on distinguishing direct versus indirect mechanisms. Notably, PRMTs regulate autophagy primarily at the level of upstream stress integration, particularly through FOXO-dependent transcription and AMPK-linked autophagic competence, thereby preventing both inadequate mitochondrial clearance and excessive, degenerative autophagy24,25,26. Through this balanced control, PRMTs determine whether mitochondrial stress resolves through adaptive renewal or progresses toward oxidative damage, bioenergetic failure, and neuromuscular degeneration.PRMT1PRMT1 functions as a central amplifier of mitochondrial biogenesis and mitophagy by integrating metabolic stress signalling in skeletal muscle. Among the PRMT family members, PRMT1 is the most abundant and extensively studied isoform in skeletal muscle and has emerged as a central regulator of mitochondrial plasticity and stress adaptation26. PRMT1 positively regulates mitochondrial biogenesis primarily through modulation of PGC1α-dependent transcriptional programmes. Direct arginine methylation of PGC1α enhances its coactivator activity, promoting expression of genes involved in oxidative phosphorylation, mitochondrial respiration and fatty acid metabolism7,73. In this context, PRMT1 amplifies PGC1α signalling downstream of AMPK activation, stabilizing oxidative gene programmes and converting transient energetic stress into durable mitochondrial remodelling. Consistent with this role, PRMT1 expression and activity are increased in response to metabolic stress, exercise and denervation, positioning PRMT1 as an amplifier of adaptive mitochondrial remodelling in muscle12,25,74.Beyond mitochondrial biogenesis, PRMT1 plays an important role in mitochondrial quality control by integrating stress-responsive transcription with selective mitophagy. Under metabolic and oxidative stress, PRMT1 can enhance FOXO transcriptional activity, promoting expression of genes involved in antioxidant defence, autophagy and mitochondrial surveillance18,24. When coupled to effective mitochondrial clearance, this FOXO-dependent response supports adaptive remodelling; however, sustained FOXO activation in the context of impaired mitophagy becomes maladaptive, driving excessive proteolysis and mitochondrial depletion. Thus, PRMT1 functions as a gain controller of FOXO output rather than as a simple activator, tuning the balance between stress adaptation and degenerative catabolism.In parallel, PRMT1 directly regulates selective mitophagy through TBK1–OPTN-dependent signalling, a pathway essential for efficient removal of damaged mitochondria under metabolic and inflammatory stress12. PRMT1 mediates methylation of TBK1 at R54, R134 and R228, and this asymmetric arginine modification is essential for TBK1 activation75. Through arginine methylation-dependent regulation of signalling components, such as TBK1, PRMT1 fine-tunes mitophagic flux, preventing accumulation of dysfunctional mitochondria that would otherwise impair bioenergetic efficiency and increase oxidative stress. Disruption of PRMT1 activity in skeletal muscle results in mitochondrial abnormalities, defective mitophagy and elevated oxidative stress, phenotypes that precede overt muscle atrophy. These mitochondrial defects are accompanied by NMJ instability and denervation-like features, highlighting a functional link between PRMT1-dependent mitochondrial surveillance and neuromuscular integrity12. Additionally, another study, conducted in cancer cells, reported that PRMT1 enhances DDX3 stability via arginine methylation, thereby promoting PINK1 expression and mitophagy, and proposed this mechanism as a molecular basis for mitochondrial function regulation76.In cardiac muscle studies, PRMT1 has been shown to attenuate excessive endoplasmic reticulum stress by promoting ATF4 methylation77. While a direct role in the UPRmt was not examined, given that ATF4 is a key transcriptional regulator of UPRmt, these findings raise the possibility that PRMT1 may indirectly influence UPRmt activity through broader regulation of ATF4-dependent stress signalling.Collectively, these findings position PRMT1 as a key integrator of multiple pathways influencing mitochondrial and cellular homeostasis, including PGC1α-mediated mitochondrial biogenesis, FOXO-dependent stress responses, PRMT1–DDX3-facilitated PINK1-linked mitophagy and PRMT1-mediated TBK1 activation; however, while PRMT1 interacts with and modulates several signalling components, a direct role for PRMT1 in activating AMPK per se has not been conclusively established. Dysregulation of PRMT1 shifts the balance from adaptive mitochondrial remodelling toward bioenergetic failure, oxidative stress and neuromuscular deterioration, positioning PRMT1 as a critical determinant of mitochondrial and neuromuscular homeostasis during ageing.CARM1 (PRMT4)CARM1 primarily regulates mitochondrial dynamics by promoting stress-induced fission and constraining mitochondrial expansion. CARM1 regulates mitochondrial homeostasis by coupling transcriptional control with post-translational regulation of mitochondrial dynamics, thereby shaping mitochondrial morphology, turnover and stress responsiveness in a context-dependent manner78,79,80. Unlike PRMT1, which primarily enhances mitochondrial biogenesis and mitophagy, CARM1 functions to constrain mitochondrial expansion while tuning dynamic remodelling and quality control78.In the nucleus, CARM1 modulates mitochondrial homeostasis through transcriptional repression of mitochondrial biogenesis programmes78. By downregulating PGC1α and TFAM while promoting expression of DNM1L (DRP1), CARM1 limits mitochondrial expansion and biases mitochondrial networks toward fission. This nuclear activity positions CARM1 as a regulator that restrains mitochondrial content while maintaining dynamic flexibility under basal and metabolic stress conditions.Under oxidative stress, CARM1 undergoes phosphorylation-dependent translocation to the cytoplasm, where it directly methylates DRP1, accelerating mitochondrial fission79. This post-translational regulation amplifies mitochondrial fragmentation and increases mitochondrial ROS production, reinforcing redox signalling. Sustained cytoplasmic CARM1 activity establishes a positive feedback loop between oxidative stress and mitochondrial fission, promoting bioenergetic inefficiency and stress-induced functional decline.Importantly, CARM1 also supports basal autophagic and mitophagic competence in coordination with metabolic signalling. Through regulation of AMPK–ULK1 and AKT–FOXO pathways, CARM1 helps ensure that mitochondrial fission is coupled to efficient turnover rather than unchecked fragmentation80. Loss of CARM1 disrupts this coordination, leading to impaired autophagic flux, accumulation of dysfunctional mitochondria and defective adaptive remodelling despite reduced mitochondrial biogenesis80. Although not conducted in muscle, this study demonstrated that CARM1-mediated arginine methylation of pontin promotes FOXO3a-dependent transcription of autophagy genes, establishing an epigenetic mechanism that enhances autophagic flux81.Collectively, CARM1 functions as a regulator of mitochondrial dynamic balance, tuning the relationship between biogenesis, fission and mitophagy in response to metabolic and oxidative stress. Dysregulation of CARM1 shifts mitochondrial networks toward excessive fragmentation and oxidative burden, particularly when fission outpaces mitochondrial clearance, thereby linking altered mitochondrial dynamics to bioenergetic failure and neuromuscular vulnerability during ageing.PRMT5PRMT5 maintains metabolic and regenerative competence by restraining excessive FOXO-driven catabolic signalling rather than directly regulating mitochondrial quality control. PRMT5 contributes to mitochondrial and neuromuscular homeostasis primarily by preserving regenerative and metabolic competence rather than by directly regulating mitochondrial dynamics82,83. Although PRMT5 is classically associated with transcriptional repression and oncogenic processes, accumulating evidence highlights an essential role in skeletal muscle progenitor maintenance and stress resilience82,83.Genetic ablation of PRMT5 in embryonic myoblasts results in progressive muscle atrophy, impaired satellite cell maintenance and premature lethality despite normal embryonic development82. Mechanistically, PRMT5 methylates FOXO1, promoting its destabilization and restraining excessive FOXO-driven autophagy and lipophagy82. Loss of PRMT5 increases total FOXO1 levels and favours its cytoplasmic accumulation, leading to premature and dysregulated autophagy, depletion of lipid droplets and impaired metabolic support in myoblasts. This imbalance compromises proliferative capacity, accelerates differentiation and restricts postnatal regenerative potential.Importantly, systemic inhibition of autophagy partially rescues lipid storage and muscle regeneration in PRMT5-deficient mice, underscoring the requirement for PRMT5-mediated restraint of FOXO-driven autophagy during muscle development and repair83. By preserving lipid reserves and metabolic flexibility, PRMT5 indirectly supports mitochondrial function during periods of high energetic demand, for example, during regeneration following injury or denervation.Additionally, PRMT5 plays a critical role in maintaining proper ATF4 splicing, which ensures stable protein levels of ATF4, a key transcription factor for UPRmt. Although a direct role of PRMT5 in UPRmt has not been demonstrated, these findings suggest that PRMT5 may be important for the expression of ATF4-dependent target genes within the UPRmt pathway84.In the context of ageing, declining regenerative capacity is a major contributor to sarcopenia and neuromuscular instability. PRMT5-dependent regulation of progenitor cell homeostasis and FOXO activity therefore shapes the cellular context in which mitochondrial quality control operates, indirectly supporting mitochondrial function while permitting appropriate mTOR reactivation during recovery. Collectively, these findings position PRMT5 as a regulator of regenerative and metabolic competence that acts upstream of mitochondrial stress to preserve long-term neuromuscular integrity.PRMT7PRMT7 supports mitochondrial function indirectly by sustaining oxidative metabolism and stress-adaptive transcriptional programmes in skeletal muscle. PRMT7 contributes to mitochondrial homeostasis in skeletal muscle primarily through indirect regulation of oxidative and stress-adaptive transcriptional programmes rather than through the direct control of mitochondrial dynamics or core quality control machinery85. In contrast to PRMT1 and CARM1, which directly modulate mitochondrial biogenesis, fission and mitophagy, PRMT7 influences mitochondrial function by shaping the muscle metabolic phenotype and its transcriptional responsiveness to energetic stress.Genetic loss of PRMT7 leads to reduced expression of PGC1α and downstream oxidative genes in skeletal muscle, resulting in a shift toward a more glycolytic muscle phenotype and diminished mitochondrial oxidative capacity86. These changes are accompanied by reduced endurance and impaired metabolic flexibility, indicating that PRMT7 supports mitochondrial energy metabolism by sustaining oxidative gene programmes. Mechanistically, PRMT7 has been linked to stress-activated signalling pathways, including p38 MAPK–ATF2, which regulates PGC1α transcription. Moreover, in vitro studies have shown that PRMT7 methylates arginine residues R548 and R753 in the C-terminal region of PGC1α, with methylation occurring preferentially at lower temperatures (≤30 °C). This temperature-dependent modification suggests a potential regulatory effect on PGC1α transcriptional activity, although a direct link between methylation and enhanced activation has not yet been demonstrated87.In addition, PRMT7 directly supports cellular tolerance through arginine methylation of HSP70 family chaperones; inhibition or loss of PRMT7 reduces HSP70 methylation and compromises resistance to proteotoxic stress88. Consequently, PRMT7 deficiency manifests primarily as reduced mitochondrial metabolic fitness rather than as defects in mitochondrial morphology or mitophagy. The combined loss of oxidative capacity and HSP70-mediated stress buffering is therefore expected to increase reliance on FOXO-dependent catabolic stress responses, lowering the threshold for AMPK–FOXO engagement.Together, these findings position PRMT7 as a permissive regulator that sets the metabolic and proteostatic baseline required for adaptive mitochondrial remodelling, complementing the more direct mitochondrial quality control functions of PRMT1 and CARM1.PRMT8PRMT8 acts as a neuron-specific regulator of mitochondrial stress tolerance and NMJ stability. PRMT8 is a neuron-enriched member of the PRMT family with predominant expression in the central nervous system, including spinal cord motor neurons, indicating a specialized role in neuronal maintenance rather than muscle-intrinsic regulation89. In vivo studies demonstrate that PRMT8 contributes to neuronal stress tolerance during ageing: genetic loss of PRMT8 reduces asymmetric dimethylarginine levels in postmitotic motor neurons, leading to premature NMJ destabilization and age-associated decline in muscle strength, accompanied by increased DNA damage and reduced CREB1 signalling90.Mechanistically, PRMT8 has been linked to the regulation of membrane lipid homeostasis and neuronal stress adaptation. Following hypoxic stress, PRMT8-knockout mice exhibit altered membrane phospholipid composition, reduced mitochondrial stress capacity as assessed by oxygen consumption-based measurements, and elevated neuroinflammatory markers, whereas PRMT8 overexpression reverses these phenotypes91. In addition, PRMT8 has been reported to possess phosphatidylcholine-hydrolyzing phospholipase activity, generating choline and phosphatidic acid, with PRMT8 loss causing abnormal dendritic arborization and motor behaviour deficits. Together, these findings support a role for PRMT8 in coupling membrane lipid metabolism to mitochondrial stress resilience and inflammatory control in neurons.Collectively, current evidence supports PRMT8 as a neuron-restricted regulator of stress tolerance that integrates arginine methylation and membrane lipid biology to maintain mitochondrial stress capacity and NMJ stability during ageing. Direct evidence linking PRMT8 to canonical mitochondrial quality control pathways remains limited, and further work will be required to define its neuronal substrates and compartment-specific functions.PRMT-mediated regulation of mitochondrial plasticity: summary overviewThe roles of PRMT family members in regulating mitochondrial quality control, metabolic signalling and stress adaptation are summarized in this section (Table 3). For each PRMT, we indicate the specific molecular targets, whether the regulation is direct or indirect, and the experimental models used, including muscle-intrinsic, neuron-specific and cancer cell studies. This compilation integrates findings from cellular, mouse and in vitro models, allowing comparison of how different PRMTs fine-tune mitochondrial biogenesis, dynamics, mitophagy, UPRmt and stress tolerance pathways. By distinguishing results from cancer cells versus physiological or neuronal contexts, the table provides a comprehensive overview of the coordinated roles of PRMTs in maintaining mitochondrial plasticity.Table 3 Roles of PRMT family members in regulating mitochondrial quality control, metabolic signalling and stress adaptation.Full size tablePRMT-regulated metabolic stress signalling in neuromuscular pathologyPathological neuromuscular conditions characterized by chronic metabolic stress, mitochondrial dysfunction and excessive ROS production, including muscle wasting syndromes, NMJ degeneration and motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), highlight the vulnerability of mitochondrial quality control mechanisms that normally preserve neuromuscular integrity92. Emerging evidence suggests that PRMT-regulated stress signalling intersects with these pathological processes.In sarcopenia and cachectic muscle wasting, sustained metabolic stress progressively overwhelms adaptive mitochondrial remodelling, resulting in impaired oxidative phosphorylation and chronic ATP insufficiency93,94. Persistent mitochondrial ROS damages respiratory components and contractile machinery while activating FOXO-dependent catabolic transcriptional programmes15,95. Although initially adaptive, prolonged FOXO activation in the absence of effective mitochondrial renewal drives excessive proteolysis and mitochondrial depletion96,97. Altered PRMT-dependent modulation of FOXO activity and autophagy, particularly involving PRMT1 and PRMT5, may further exacerbate muscle weakness and functional decline25,79. NMJs represent a focal point of vulnerability due to their high energetic demand and dependence on localized mitochondrial support47,48. In pathological states associated with altered PRMT-regulated stress signalling, particularly involving PRMT1-dependent control of mitochondrial quality and mitophagy and CARM1-mediated regulation of mitochondrial dynamics, subsynaptic mitochondria exhibit heightened ROS accumulation and impaired turnover12,77. In parallel, neuron-restricted PRMT8 has been shown to support NMJ stability during ageing by promoting stress tolerance in postmitotic motor neurons; loss of PRMT8 leads to premature NMJ destabilization and age-associated muscle weakness, indicating that neuronal stress buffering contributes to NMJ resilience87. Notably, NMJ degeneration frequently precedes overt myofibre atrophy, indicating that neuromuscular failure is an early consequence of mitochondrial stress rather than a secondary effect of muscle loss8,98,99. Reduced neuromuscular activity further exacerbates mitochondrial dysfunction within muscle fibres, establishing a feed-forward cycle of degeneration12,100.Motor neuron diseases, particularly ALS, highlight the consequences of unresolved mitochondrial stress in neurons101,102. Motor neurons are exceptionally sensitive to defects in mitochondrial transport, membrane potential maintenance and redox homeostasis. In ALS, mitochondrial depolarization, impaired axonal transport and excessive ROS accumulation compromise synaptic vesicle cycling and axonal integrity, leading to early NMJ denervation followed by motor neuron degeneration101. Consistent with this vulnerability, genetic and molecular studies of ALS converge on selective autophagy and mitophagy pathways as critical determinants of motor neuron survival, with multiple ALS-associated genes encoding components of mitochondrial surveillance machinery102. Complementing these pathways, PRMT8 functions as a neuron-specific regulator of stress tolerance, coupling arginine methylation and membrane phospholipid homeostasis to mitochondrial stress capacity and inflammatory control, thereby influencing motor neuron resilience under chronic stress80.Within this context, PRMT1 emerges as a mechanistically relevant regulator linking mitochondrial quality control to ALS-associated proteostasis defects. In motor neurons, PRMT1-dependent arginine methylation supports mitochondrial integrity and stress adaptation; consistent with this, our recent work demonstrates that motor neuron-specific PRMT1 knockout impairs mitochondrial structure and function and leads to motor neuron degeneration, highlighting a cell-autonomous requirement for PRMT1 in mitochondrial maintenance103. PRMT1 also methylates the RNA-binding protein FUS, promoting its nuclear localization and limiting pathological cytoplasmic aggregation104. ALS-associated FUS mutations impair PRMT1-dependent methylation, resulting in aberrant cytoplasmic accumulation, persistent stress granules and increased mitochondrial stress. In parallel, PRMT1 regulates selective mitophagy through TBK1–OPTN-dependent signalling in skeletal muscle, a pathway genetically and functionally implicated in ALS105. Altered PRMT1 activity therefore provides a mechanistic bridge between defective mitophagy, perturbed RNA and protein homeostasis, and mitochondrial dysfunction in motor neurons.Metabolic disorders further amplify mitochondrial stress across neuromuscular tissues. Insulin resistance and lipid overload reduce metabolic flexibility, increase ROS generation and suppress adaptive mitochondrial renewal106,107. In this context, altered PRMT-regulated stress signalling, including pathways involving PRMT1, PRMT5 and PRMT7, may lower the threshold for mitochondrial failure, NMJ instability and progressive motor unit loss12,82,86,108.Collectively, muscle wasting, NMJ degeneration and motor neuron disease share a common pathological triad of bioenergetic insufficiency, oxidative stress and proteostatic imbalance. Failure of PRMT-regulated metabolic stress signalling converts adaptive mitochondrial responses into self-propagating degenerative cycles. In motor neurons, PRMT8-dependent stress tolerance mechanisms act in parallel with PRMT1-mediated mitochondrial quality control to delay NMJ destabilization and neuronal degeneration, positioning PRMT-regulated pathways as unifying determinants of neuromuscular pathology and compromised healthspan.PRMTs as multi-layered regulators of muscle secretory networks and neuromuscular functionSkeletal muscle serves as a principal endocrine organ, and muscle-derived secretory factors have long represented a focal point in ageing and exercise physiology research. Myokines and inflammatory mediators are not only directly implicated in muscle atrophy and functional decline but also mediate the systemic benefits of exercise109. However, to date, direct experimental evidence delineating the role of PRMTs in regulating the expression and secretion of these muscle-derived factors remains limited, with most insights derived from indirect mechanistic frameworks.PRMT1 has been shown to methylate the transcriptional coactivator PGC1α, modulating its transcriptional activity73. PGC1α, in turn, governs the expression of key myokines, including irisin and VEGF110,111. PRMT7 has been implicated in the regulation of oxidative metabolism and mitochondrial function in skeletal muscle, with deficiency leading to impaired metabolic capacity and reduced exercise performance86. These phenotypic consequences mirror those observed with PGC1α dysfunction, suggesting that PRMT7 may indirectly influence the myokine secretory milieu through shared metabolic regulatory networks.In addition, PRMT1, CARM1 and PRMT5 have been demonstrated across multiple experimental systems to modulate inflammatory cytokine expression via the NF-κB signalling pathway. Specifically, PRMT1 mediates asymmetric arginine methylation of NF-κB p65 (RelA) at R30, attenuating DNA binding and transcriptional activity, thereby indirectly regulating NF-κB-dependent cytokine expression in muscle112. Conversely, PRMT5 methylates distinct arginine residues on NF-κB p65, enhancing its transcriptional activity and promoting CXCL11 expression under TNF and IFNγ stimulation113. CARM1 functions as a transcriptional coactivator through histone arginine methylation, modulating chromatin accessibility, and its protein levels in skeletal muscle respond dynamically to exercise stimuli, regulating genes implicated in metabolism and energy homeostasis114. Collectively, these data suggest that PRMT family enzymes may indirectly influence myokine expression by integrating NF-κB-dependent inflammatory signalling, transcriptional regulation and metabolic state in skeletal muscle.Although the majority of mechanistic evidence originates from immune cells and alternative model systems, studies in human skeletal muscle demonstrate that PRMT expression and enzymatic activity are modulated in response to exercise85. These observations underscore the potential for PRMT-mediated regulation to shape the myokine secretory environment under physiologically relevant conditions.Overall, PRMT-mediated arginine methylation establishes a multi-layered regulatory network, encompassing the PGC1α metabolic axis (PRMT1–PRMT7), the NF-κB inflammatory axis (PRMT1–PRMT5) and the CARM1 metabolic–transcriptional axis, which may collectively exert indirect control over muscle-derived secretory factors and neuromuscular signalling.A compendium of PRMT-mediated methylome profilesPRMT research initially focused on individual proteins or specific mechanisms but recent studies have shifted toward understanding integrated arginine methylation (methylome) regulation within cells (Table 4). PRMT1 knockdown analyses in HEK293 cells revealed approximately 127 arginine methylation sites on RNA-binding and metabolism-related proteins, with some substrates showing compensatory methylation by other PRMTs115. Recent in vivo methylproteomic profiling has defined the prevalence of arginine methylation in skeletal muscle independent of cell line models. Using a comprehensive enrichment and liquid chromatography–mass spectrometry approach, over 1,150 arginine methylation sites were identified on 313 proteins in wild-type quadriceps muscle, and CARM1 skeletal muscle-specific knockout was shown to remodel both the methylome and transcriptome, with functional consequences for muscle phenotype114. Meanwhile, in acute myeloid leukaemia-derived cancer cells (THP-1, MOLM-13), PRMT5 profiling under CRISPR-knockdown conditions revealed methylation changes in splicing factors and metabolism-related proteins through global methylome and proteome analyses116. In addition, comparative studies of CARM1, PRMT5 and PRMT7 in HEK293 cells identified key substrates involved in RNA splicing, cell growth and metabolic pathways, with some substrates shared across PRMT family members117. Finally, PRMT5 SDMA substrates were identified using ETD-based proteomic analysis in HeLa cells, suggesting that PRMT-mediated arginine methylation plays a crucial role in regulating cellular functional networks, including RNA processing, metabolism and mitochondrial function118.Table 4 PRMT substrate profiling and functional insights from methylome analyses.Full size tableThese studies collectively provide a foundation for understanding the systemic role of PRMT-mediated arginine methylation at the cellular functional network level. Although systematic methylome data in neural and muscle tissues remain limited, future studies targeting these tissues are expected to provide new insights into PRMT mechanisms specific to the neuromuscular system.Therapeutic perspectives and concluding remarks: restoring mitochondrial stress adaptation in neuromuscular pathologyPathological neuromuscular conditions, such as sarcopenia, muscle wasting syndromes and motor neuron diseases, share a common failure of mitochondrial stress adaptation rather than isolated loss of muscle mass or neurons7,8,119. Across these conditions, chronic metabolic stress, impaired mitochondrial quality control and excessive ROS production converge to drive bioenergetic insufficiency, proteostatic imbalance, NMJ instability and progressive functional decline7,8,30,119. Therapeutic strategies must therefore address the underlying stress-adaptation failure that links mitochondrial dysfunction to neuromuscular pathology.This disease-centric perspective has shifted therapeutic focus toward restoration of mitochondrial quality control and metabolic resilience. Exercise remains the most effective intervention across ageing and disease contexts, improving muscle strength, neuromuscular transmission and motor unit stability120,121. Mechanistically, exercise activates AMPK, enhances PGC1α-dependent mitochondrial biogenesis, promotes selective autophagy and mitophagy, and reduces pathological ROS accumulation, processes that are compromised in sarcopenia, cachexia and motor neuron disease122,123,124. Importantly, many of these adaptive responses intersect with PRMT-regulated signalling pathways, positioning arginine methylation as a modifiable layer of neuromuscular stress resilience.From a translational standpoint, PRMTs emerge as regulators of pathological thresholds rather than simple therapeutic targets. In disease states, dysregulated PRMT activity amplifies FOXO-driven catabolism, impairs selective mitophagy, promotes maladaptive mitochondrial fragmentation or reduces baseline oxidative capacity, thereby accelerating neuromuscular degeneration12,25,79,125. Consequently, global inhibition of PRMTs is unlikely to be beneficial. Nevertheless, numerous compounds have been developed focused only on PRMT inhibition as potential anticancer therapies, whereas pharmacological activators or inducers of PRMTs remain exceedingly rare, even for other indications (Tables 5 and 6). Considering the critical role of PRMTs in maintaining NMJs, muscle metabolism and heart function, administering PRMT inhibitors to patients with cancer could potentially exacerbate cancer cachexia, a condition characterized by severe muscle wasting12,25,77,86. Precision strategies aimed at restoring balanced PRMT-dependent signalling may therefore be required. These include enhancing PRMT1-dependent mitochondrial renewal and stress tolerance in both muscle and motor neurons, preserving PRMT5-mediated restraint of excessive autophagy during regeneration, limiting chronic CARM1-driven mitochondrial fragmentation under oxidative stress, and restoring PRMT7-dependent oxidative capacity to improve metabolic flexibility in ageing muscle12,25,79,86.Table 5 PRMT-targeting inhibitors: pharmacological mechanism, disease context and clinical phase.Full size tableTable 6 Direct and indirect activators of PRMT1 and CARM1.Full size tableCrucially, pathological conditions such as ALS underscore the importance of mitochondrial quality control in neuronal survival. Convergence of ALS-linked genes on selective autophagy and mitophagy pathways, together with PRMT1-dependent regulation of FUS and mitochondrial surveillance, highlights mitochondrial stress buffering as a shared vulnerability across neuromuscular diseases12,104. Therapeutic modulation of PRMT-regulated pathways may therefore offer a means to restore mitochondrial resilience across both muscle and motor neuron compartments.In conclusion, sarcopenia and neuromuscular degeneration arise from the breakdown of an integrated mitochondrial stress-adaptation network spanning muscle fibres, satellite cells and motor neurons. This Review positions PRMTs as regulatory nodes within metabolic and stress-responsive signalling networks that converge on AMPK, FOXO and mTOR pathways, functioning as molecular rheostats that shape adaptive versus degenerative responses to mitochondrial stress (Fig. 4). Most mechanistic insights discussed here are derived from stress-related or disease-related models, and direct causal evidence in the context of physiological ageing remains limited. Framing neuromuscular ageing and disease through this PRMT-regulated metabolic lens provides a unifying conceptual framework and highlights new opportunities to preserve neuromuscular function, delay degeneration and extend healthspan in pathological contexts.Fig. 4: PRMTs are molecular rheostats for the neuromuscular system.Full size imageStress signals, including exercise, inflammation and denervation, stimulate the neuromuscular system, activating diverse molecular signalling and metabolic pathways. Protein arginine methyltransferases (PRMTs) are regulated in a stress-responsive manner, and their dysregulation disrupts downstream pathways, including protein arginine methylation, AMP-activated protein kinase (AMPK)–Forkhead box O (FOXO)–mechanistic target of rapamycin (mTOR) metabolic signalling, and mitochondrial homeostasis, affecting not only cellular metabolic homeostasis but also systemic metabolic fitness across tissues. 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Figures were created with Biorender.com.Author informationAuthors and AffiliationsDepartment of Molecular Cell Biology, Sungkyunkwan University, Suwon, Republic of KoreaJu-Hyeon Bae, Chang-Lim You & Jong-Sun KangDepartment of Metabiohealth, Sungkyunkwan University, Suwon, Republic of KoreaJeongmin Park & Jong-Sun KangAuthorsJu-Hyeon BaeView author publicationsSearch author on:PubMed Google ScholarChang-Lim YouView author publicationsSearch author on:PubMed Google ScholarJeongmin ParkView author publicationsSearch author on:PubMed Google ScholarJong-Sun KangView author publicationsSearch author on:PubMed Google ScholarCorresponding authorCorrespondence to Jong-Sun Kang.Ethics declarationsCompeting interestsThe authors declare no conflicts of interest.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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