bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024–12–01
35 papers selected by
Anna Vainshtein, Craft Science Inc.



  1. Nat Commun. 2024 Nov 25. 15(1): 10210
      Inhibiting glycogen synthase kinase 3 (GSK3) improves muscle function, metabolism, and bone health in many diseases and conditions; however, whether GSK3 should be targeted for Duchenne muscular dystrophy (DMD), a severe muscle wasting disorder with no cure, remains unknown. Here, we show the effects of GSK3 inhibition in male DBA/2J (D2) and C57BL/10 (C57) mdx mice. Treating D2 mdx mice with GSK3 inhibitors alone or in combination with aerobic exercise improves muscle strength, endurance, and morphology, attenuates the hypermetabolic phenotype, and enhances insulin sensitivity. GSK3 inhibition in C57 mdx mice also improves muscle fatigue resistance and increases cage ambulation. Moreover, muscle-specific GSK3 knockdown in mdx mice augments muscle force production and endurance. In both mdx strains, GSK3 inhibition increases bone mineral content and density. Overall, these improvements to muscle, metabolic, and bone health with GSK3 inhibition in mdx mice may have clinical implications for patients with DMD, where the current standard of care, glucocorticoids, delay the loss of ambulation but increase the risk for insulin resistance and osteoporosis. Along with our observation of lowered β-catenin content in DMD myoblasts, a known cellular target for GSK3, this study provides ample evidence in support of inhibiting GSK3 for this disease.
    DOI:  https://doi.org/10.1038/s41467-024-53886-y
  2. Free Radic Biol Med. 2024 Nov 22. pii: S0891-5849(24)01075-X. [Epub ahead of print]
      Skeletal muscle has a high regenerative capacity due to its resident adult muscle stem cells (MuSCs), which can repair damaged tissue by forming myofibres de novo. Stem cell dependent regeneration is critical for maintaining skeletal muscle health, and different conditions can draw heavily on MuSC support to preserve muscle function, including metabolic diseases such as diabetes. The global incidence and burden of diabetes is increasing, and skeletal muscle is critical for maintaining systemic metabolic homeostasis and improving outcomes for diabetic patients. Thus, poor muscle health in diabetes, termed diabetic myopathy, is an important complication that must be addressed. The health of MuSCs is also affected by diabetes, responsible for the poor muscle regenerative capacity and contributing to the functional decline in diabetic patients. Here, we review the impact of diabetes and metabolic disease on MuSCs and skeletal muscle, including potential mechanisms for impaired muscle regeneration and MuSC dysfunction, and how these deficits could be addressed.
    Keywords:  Diabetes; Metabolic disease; Metabolism; Muscle regeneration; Muscle stem cell
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.041
  3. Res Sq. 2024 Nov 12. pii: rs.3.rs-4997138. [Epub ahead of print]
      A human model of unilateral endurance versus resistance exercise, in conjunction with deep phosphoproteomic analyses, was used to identify exercise mode-specific phosphorylation events. Among the outcomes, a resistance exercise-specific cluster of events was identified, and a multitude of bioinformatic- and literature-based predictions suggested that this was mediated by prolonged activation of a pathway involving MKK3b/6, p38, MK2, and mTORC1. Follow-up studies in humans and mice provide consistent support for the predictions and also revealed that resistance exercise-induced signaling through MKK3b and the induction of protein synthesis are highly correlated events (R = 0.87). Moreover, genetic activation of MKK3b/6 in skeletal muscles was sufficient to induce signaling through the members of the resistance exercise-specific pathway, as well as an increase in protein synthesis and fiber size. Thus, we propose that we have identified some of the core components of a signaling pathway that drives the growth-promoting effects of resistance exercise.
    DOI:  https://doi.org/10.21203/rs.3.rs-4997138/v1
  4. Cell Metab. 2024 Nov 23. pii: S1550-4131(24)00417-0. [Epub ahead of print]
      Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
    Keywords:  MCU; MCUR1; aging; calcium signaling; endurance; energy; fatigue; mitochondria; polyphenols; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.021
  5. Int J Mol Sci. 2024 Nov 19. pii: 12415. [Epub ahead of print]25(22):
      Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system (CNS) but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMNΔ7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN∆7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. We provide essential new ultrastructural data on focal and segmental lesions in the myofibrillar contractile apparatus. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation-contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the growing body of evidence indicating the existence of intrinsic alterations in the skeletal muscle in SMA and further reinforces the relevance of this peripheral tissue as a key therapeutic target for the disease.
    Keywords:  SMA; SMN∆7 mice; actin filaments; mitochondria; sarcomere; skeletal muscle; triads
    DOI:  https://doi.org/10.3390/ijms252212415
  6. Free Radic Biol Med. 2024 Nov 27. pii: S0891-5849(24)01080-3. [Epub ahead of print]
      One of the most critical factors impacting healthspan in the elderly is the loss of muscle mass and function, clinically referred to as sarcopenia. Muscle atrophy and weakness lead to loss of mobility, increased risk of injury, metabolic changes and loss of independence. Thus, defining the underlying mechanisms of sarcopenia is imperative to enable the development of effective interventions to preserve muscle function and quality in the elderly and improve healthspan. Over the past few decades, understanding the roles of mitochondrial dysfunction and oxidative stress has been a major focus of studies seeking to reveal critical molecular pathways impacted during aging. In this review, we will highlight how oxidative stress might contribute to sarcopenia by discussing the impact of oxidative stress on the loss of innervation and alteration in the neuromuscular junction (NMJ), on muscle mitochondrial function and atrophy pathways, and finally on muscle contractile function.
    Keywords:  Aging; Mitochondria; Neuromuscular Junction; Sarcopenia; Skeletal Muscle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.046
  7. Int J Mol Sci. 2024 Nov 20. pii: 12463. [Epub ahead of print]25(22):
      Skeletal muscle atrophy is a major health concern, severely affecting the patient's mobility and life quality. In the pathological process of skeletal muscle atrophy, with the progressive decline in muscle quality, strength, and function, the incidence of falling, fracture, and death is greatly increased. Unfortunately, there are no effective treatments for this devastating disease. Thus, it is imperative to investigate the exact pathological molecular mechanisms underlying the development of skeletal muscle atrophy and to identify new therapeutic targets. Decreased muscle mass, strength, and muscle fiber cross-sectional area are typical pathological features and manifestations of skeletal muscle atrophy. Ferroptosis, an emerging type of programmed cell death, is characterized by iron-dependent oxidative damage, lipid peroxidation, and reactive oxygen species accumulation. Notably, the understanding of its role in skeletal muscle atrophy is emerging. Ferroptosis has been found to play an important role in the intricate interplay between the pathological mechanisms of skeletal muscle atrophy and its progression caused by multiple factors. This provides new opportunities and challenges in the treatment of skeletal muscle atrophy. Therefore, we systematically elucidated the ferroptosis mechanism and its progress in skeletal muscle atrophy, aiming to provide a comprehensive insight into the intricate relationship between ferroptosis and skeletal muscle atrophy from the perspectives of iron metabolism and lipid peroxidation and to provide new insights for targeting the pathways related to ferroptosis and the treatment of skeletal muscle atrophy.
    Keywords:  Xc-GSH-GPX4 pathway; ferroptosis; iron metabolism; lipid peroxidation; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/ijms252212463
  8. Int J Mol Sci. 2024 Nov 06. pii: 11901. [Epub ahead of print]25(22):
      Autophagy maintains the stability of eukaryotic cells by degrading unwanted components and recycling nutrients and plays a pivotal role in muscle regeneration by regulating the quiescence, activation, and differentiation of satellite cells. Effective muscle regeneration is vital for maintaining muscle health and homeostasis. However, under certain disease conditions, such as aging, muscle regeneration can fail due to dysfunctional satellite cells. Dysregulated autophagy may limit satellite cell self-renewal, hinder differentiation, and increase susceptibility to apoptosis, thereby impeding muscle regeneration. This review explores the critical role of autophagy in muscle regeneration, emphasizing its interplay with apoptosis and recent advances in autophagy research related to diseases characterized by impaired muscle regeneration. Additionally, we discuss new approaches involving autophagy regulation to promote macrophage polarization, enhancing muscle regeneration. We suggest that utilizing cell therapy and biomaterials to modulate autophagy could be a promising strategy for supporting muscle regeneration. We hope that this review will provide new insights into the treatment of muscle diseases and promote muscle regeneration.
    Keywords:  apoptosis; autophagy; cell therapy; muscle regeneration; satellite cells
    DOI:  https://doi.org/10.3390/ijms252211901
  9. PLoS One. 2024 ;19(11): e0313679
      Peripheral nerve injury may result in muscle atrophy and impaired motor function recovery, and numerous pieces of evidence indicate that long noncoding RNAs (lncRNAs) play crucial roles in skeletal muscle regeneration. Our preliminary sequencing results showed that LNC_000280 was significantly down-regulated in denervated mouse skeletal muscle and we hypothesized that LNC_000280 may play an important role in skeletal muscle regeneration. In this research, flow cytometry and EdU staining results showed that overexpression of LNC_000280 promoted the proliferation of C2C12, while knockdown LNC_000280 had the opposite effect. Knockdown LNC_000280 inhibited the differentiation of C2C12 cells. LNC_000280 regulated the expression of proliferation genes (Cdk2, Cdc27) and differentiation genes (MyoG, MyoD). GO analysis and PPI network of LNC_000280 target genes showed that LNC_000280 mainly regulates skeletal muscle cell metabolism, mitochondrial and muscle growth. Idh2, Klhl31, Agt, and Gpt2 may be important downstream targets for its function. Therefore, we believe that that LNC_000280 can regulate the proliferation and differentiation of myoblasts by regulating gene expression.
    DOI:  https://doi.org/10.1371/journal.pone.0313679
  10. Am J Physiol Cell Physiol. 2024 Nov 29.
      A complication of type 1 diabetes mellitus (T1DM) is diabetic myopathy which includes reduced regenerative capacity of skeletal muscle. Sphingolipids are a diverse family of lipids with roles in skeletal muscle regeneration. Some studies have found changes in sphingolipid species levels in T1DM, however, the effect of T1DM on a sphingolipid panel in regenerating skeletal muscle has not been examined. Wild type (WT) and diabetic Ins2Akita+/- (Akita) mice received cardiotoxin-induced muscle injury in their left quadriceps, gastrocnemius-plantaris-soleus, and tibialis anterior muscles with the contralateral muscles serving as uninjured controls. Muscles were collected at 1, 3, 5, or 7 days post-injury. In regenerating muscle from Akita mice, lipid staining with Bodipy 493/503 revealed increased intramyocellular and total lipids as well as perilipin-1-positive cell numbers as compared with WT. Liquid chromatography-mass spectrometry of quadriceps was used to identify sphingolipid levels in skeletal muscle. The C22:0 and C24:0 ceramides were significantly elevated in uninjured Akita, while ceramide C24:1 was decreased in injured Akita compared to WT. Ceramide-1-phosphate was increased in Akita compared to WT regardless of injury, while sphingosine 1-phosphate (S1P) was elevated with injury in WT but this response was muted in Akita mice. Western blotting of key enzymes involved in sphingolipid metabolism revealed S1P lyase, the enzyme which degrades S1P irreversibly, was significantly elevated in the injured muscle in Akita mice during regeneration, in accordance with lower S1P levels. This mouse model of T1DM demonstrates sphingolipidomic changes that may contribute to delayed muscle regeneration.
    Keywords:  Diabetic Myopathy; Skeletal Muscle Regeneration; Sphingolipids; Sphingosine-1-phosphate; Type 1 Diabetes Mellitus
    DOI:  https://doi.org/10.1152/ajpcell.00158.2024
  11. Int J Mol Sci. 2024 Nov 14. pii: 12216. [Epub ahead of print]25(22):
      We examined changes in skeletal muscle protein lactylation and acetylation in response to acute resistance exercise, chronic resistance training (RT), and a single endurance cycling bout. Additionally, we performed in vitro experiments to determine if different sodium lactate treatments affect myotube protein lactylation and acetylation. The acute and chronic RT study (12 college-aged participants) consisted of 10 weeks of unilateral leg extensor RT with vastus lateralis (VL) biopsies taken at baseline, 24 h following the first RT bout, and the morning of the last day of the RT bout. For the acute cycling study (9 college-aged participants), VL biopsies were obtained before, 2 h after, and 8 h after 60 min of cycling. For in vitro experiments, C2C12 myotubes were treated with varying levels of sodium lactate, including LOW (1 mM for 24 h), HIGH (10 mM for 24 h), and PULSE (10 mM for 30 min followed by 1 mM for 23.5-h). Neither acute nor chronic RT significantly affected nuclear or cytoplasmic protein lactylation. However, cytoplasmic protein acetylation was significantly reduced following one RT bout (-15%, p = 0.002) and chronic RT (-16%, p = 0.006). Cycling did not acutely alter post-exercise global protein lactylation or acetylation patterns. Lastly, varying 24 h lactate treatments did not alter nuclear or cytoplasmic protein lactylation or acetylation, cytoplasmic protein synthesis levels, or myotube diameters. These findings continue to support the idea that exercise induces more dynamic changes in skeletal muscle protein acetylation, but not lactylation. However, further human research with more sampling timepoints and a lactylomics approach are needed to determine if, at all, different exercise modalities affect skeletal muscle protein lactylation.
    Keywords:  hypertrophy; protein acetylation; protein lactylation; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms252212216
  12. Mol Aspects Med. 2024 Nov 25. pii: S0098-2997(24)00081-5. [Epub ahead of print]100 101322
      Function declines throughout life although phenotypical manifestations in terms of frailty or disability are only seen in the later periods of our life. The causes underlying lifelong function decline are the aging process "per se", chronic diseases, and lifestyle factors. These three etiological causes result in the deterioration of several organs and systems which act synergistically to finally produce frailty and disability. Regardless of the causes, the skeletal muscle is the main organ affected by developing sarcopenia. In the first section of the manuscript, as an introduction, we review the quantitative and qualitative age-associated skeletal muscle changes leading to frailty and sarcopenia and their impact in the quality of life and independence in the elderly. The reversibility of frailty and sarcopenia are discussed in the second and third sections of the manuscript. The most effective intervention to delay and even reverse frailty is exercise training. We review the role of different training programs (resistance exercise, cardiorespiratory exercise, multicomponent exercise, and real-life interventions) not only as a preventive but also as a therapeutical strategy to promote healthy aging. We also devote a section in the text to the sexual dimorphic effects of exercise training interventions in aging. How to optimize the skeletal muscle anabolic response to exercise training with nutrition is also discussed in our manuscript. The concept of anabolic resistance and the evidence of the role of high-quality protein, essential amino acids, creatine, vitamin D, β-hydroxy-β-methylbutyrate, and Omega-3 fatty acids, is reviewed. In the last section of the manuscript, the main genetic interventions to promote robustness in preclinical models are discussed. We aim to highlight the molecular pathways that are involved in frailty and sarcopenia. The possibility to effectively target these signaling pathways in clinical practice to delay muscle aging is also discussed.
    DOI:  https://doi.org/10.1016/j.mam.2024.101322
  13. JCI Insight. 2024 Nov 26. pii: e182842. [Epub ahead of print]
      Both CO2 retention, or hypercapnia, and skeletal muscle dysfunction predict higher mortality in critically ill patients. Mechanistically, muscle injury and reduced myogenesis contribute to critical illness myopathy, and while hypercapnia causes muscle wasting, no research has been conducted on hypercapnia-driven dysfunctional myogenesis in vivo. Autophagy flux regulates myogenesis by supporting muscle stem cell -satellite cell- activation, and previous data suggests that hypercapnia inhibits autophagy. We tested whether hypercapnia worsens satellite cell autophagy flux and myogenic potential, and if autophagy induction reverses these deficits. Satellite cell transplantation and lineage tracing experiments showed that hypercapnia undermines satellite cells activation, replication, and myogenic capacity. Bulk and single cell sequencing analyses indicated that hypercapnia disrupts autophagy, senescence, and other satellite cells programs. Autophagy activation was reduced in hypercapnic cultured myoblasts, and autophagy genetic knockdown phenocopied these changes in vitro. Rapamycin stimulation led to AMPK activation and downregulation of the mTOR pathway, which are both associated with accelerated autophagy flux and cell replication. Moreover, hypercapnic mice receiving rapamycin showed improved satellite cells autophagy flux, activation, replication rate, and post transplantation myogenic capacity. In conclusion, we have shown that hypercapnia interferes with satellite cell activation, autophagy flux and myogenesis, and systemic rapamycin administration improved these outcomes.
    Keywords:  Autophagy; Mouse stem cells; Pulmonology; Respiration
    DOI:  https://doi.org/10.1172/jci.insight.182842
  14. Int J Mol Sci. 2024 Nov 20. pii: 12478. [Epub ahead of print]25(22):
      Lowered muscle regenerative capacity in the elderly greatly contributes to the development of multiple diseases. The specific roles of long noncoding RNAs (lncRNAs) in muscle regenerative capacity during aging remain unknown. Here, we identify an elevated lncRNA (lncRNA-3), in association with reduced MyoD expression and suppressed muscle regenerative capacity, in the skeletal muscle of aged mice. LncRNA-3 could interact with both the MyoD1 promoter and RbAp46/48, a subunit of Polycomb repressive complex 2 (PRC2). LncRNA-3 could recruit PRC2 to the MyoD1 promoter and enhance the MyoD1 silencing, which, in turn, suppressed the muscle regenerative capacity. Muscle-specific lncRNA-3 knockdown could restore the muscle regenerative capacity in the aged mice. Exogenous RbAp46/48 binding motif (Rb-motif-2) treatment in skeletal muscle could compete for the lncRNA-3 binding, and therefore, enhance the muscle regenerative capacity in the aged mice. Taken together, lncRNA-3 requires PRC2 for MyoD1 silencing to suppress muscle regenerative capacity during aging. These findings provide a novel therapeutic target and a new strategy to elevate the muscle regenerative capacity in the aged population.
    Keywords:  MyoD1; RbAp46/48; long noncoding RNA; muscle regeneration; polycomb repressive complex 2
    DOI:  https://doi.org/10.3390/ijms252212478
  15. Trends Endocrinol Metab. 2024 Nov 28. pii: S1043-2760(24)00274-1. [Epub ahead of print]
      Lipid droplets (LDs) are dynamic organelles that communicate with other cellular components to orchestrate energetic homeostasis and signal transduction. In skeletal muscle, the presence and importance of LDs have been widely studied in myofibers of both rodents and humans under physiological conditions and in metabolic disorders. However, the role of LDs in myogenic stem cells has only recently begun to be unveiled. In this review we briefly summarize the process of LD biogenesis and degradation in the most prevalent model. We then review recent knowledge on LDs in skeletal muscle and muscle stem cells. We further introduce advanced methodologies for LD imaging and mass spectrometry that have propelled our understanding of the dynamics and heterogeneity of LDs.
    Keywords:  lipid droplets; lipid mediators; muscle stem cells; skeletal muscle
    DOI:  https://doi.org/10.1016/j.tem.2024.10.006
  16. Cell Signal. 2024 Nov 24. pii: S0898-6568(24)00491-1. [Epub ahead of print]126 111516
      The EP4 (prostaglandin E2) receptor plays a crucial role in myogenesis and skeletal muscle regeneration, yet its involvement in regulating insulin-dependent metabolic pathways is not well characterised. Our research investigates the expression of EP4 in rat skeletal L6 myotubes and its impact on insulin signalling. We found that activation of EP4 by selective agonists disrupts insulin signalling and insulin-stimulated glucose uptake. This impairment is associated with enhanced pro-inflammatory NF-κB signalling, a process that can be attenuated by EP4 antagonists. Importantly, EP4 antagonism also reduces NF-κB activation induced by palmitate and the associated reduction in insulin signalling, an effect not replicated by antagonists of EP1, EP2, or EP3 receptors. These observations indicate that the EP4 receptor is a modulator of insulin action and that it contributes to fatty-acid-induced insulin resistance in skeletal muscle cells. Our findings suggest that EP4 could be a potential therapeutic target for managing insulin resistance.
    Keywords:  Cyclooxygenase-2; Glucose transport; NFkB; Prostaglandin E2
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111516
  17. Eur J Appl Physiol. 2024 Nov 28.
      Recovery methods, such as thermal interventions, have been developed to promote optimal recovery and maximize long-term training adaptations. However, the beneficial effects of these recovery strategies remain a source of controversy. This narrative review aims to provide a detailed understanding of how cold and heat interventions impact long-term training adaptations. Emphasis is placed on skeletal muscle adaptations, particularly the involvement of signaling pathways regulating protein turnover, ribosome and mitochondrial biogenesis, as well as the critical role of satellite cells in promoting myofiber regeneration following atrophy. The current literature suggests that cold interventions can blunt molecular adaptations (e.g., protein synthesis and satellite cell activation) and oxi-inflammatory responses after resistance exercise, resulting in diminished exercise-induced hypertrophy and lower gains in isometric strength during training protocols. Conversely, heat interventions appear promising for mitigating skeletal muscle degradation during immobilization and atrophy. Indeed, heat treatments (e.g., passive interventions such as sauna-bathing or diathermy) can enhance protein turnover and improve the maintenance of muscle mass in atrophic conditions, although their effects on uninjured skeletal muscles in both humans and rodents remain controversial. Nonetheless, heat treatment may serve as an important tool for attenuating atrophy and preserving mitochondrial function in immobilized or injured athletes. Finally, the potential interplay between exercise, thermal interventions and epigenetics is discussed. Future studies must be encouraged to clarify how repeated thermal interventions (heat and cold) affect long-term exercise training adaptations and to determine the optimal modalities (i.e., method of application, temperature, duration, relative humidity, and timing).
    Keywords:  Cryotherapy; Exercise; Heat treatment; Protein synthesis; Resistance and endurance training; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00421-024-05642-9
  18. Mol Med. 2024 Nov 30. 30(1): 238
      The fibrogenic conversion of satellite cells contributes to the atrophy and fibrosis of skeletal muscle, playing a significant role in the pathogenesis of age-related sarcopenia. Melatonin, a hormone secreted by the pineal gland, exhibits anti-aging and anti-fibrotic effects in various conditions. However, the effect of melatonin on satellite cell fate and age-related sarcopenia remains under-explored. Here, we report that melatonin treatment mitigated the loss of muscle mass and strength in aged mice, replenished the satellite cell pool and curtailed muscle fibrosis. When primary SCs were cultured in vitro and subjected to aging induction via D-galactose, they exhibited a diminished myogenic potential and a conversion from myogenic to fibrogenic lineage. Notably, melatonin treatment effectively restored the myogenic potential and inhibited this lineage conversion. Furthermore, melatonin attenuated the expression of the fibrogenic cytokine, transforming growth factor-β1, and reduced the phosphorylation of its downstream targets Smad2/3 both in vivo and in vitro. In summary, our findings show melatonin's capacity to counteract muscle decline and inhibit fibrogenic conversion in aging SCs and highlight its potential therapeutic value for age-related sarcopenia.
    Keywords:  Aging; Melatonin; Muscular fibrosis; Sarcopenia; Satellite cell
    DOI:  https://doi.org/10.1186/s10020-024-00998-2
  19. Cells. 2024 Nov 18. pii: 1903. [Epub ahead of print]13(22):
      Insulin resistance, stem cell dysfunction, and muscle fiber dystrophy are all age-related events in skeletal muscle (SKM). However, age-related changes in insulin isoforms and insulin receptors in myogenic progenitor satellite cells have not been studied. Since SKM is an extra-pancreatic tissue that does not express mature insulin, we investigated the levels of insulin receptors (INSRs) and a novel human insulin upstream open reading frame (INSU) at the mRNA, protein, and anatomical levels in Baltimore Longitudinal Study of Aging (BLSA) biopsied SKM samples of 27-89-year-old (yrs) participants. Using RT-qPCR and the MS-based selected reaction monitoring (SRM) assay, we found that the levels of INSR and INSU mRNAs and the proteins were positively correlated with the age of human SKM biopsies. We applied RNAscope fluorescence in situ hybridization (FISH) and immunofluorescence (IF) to SKM cryosections and found that INSR and INSU were co-localized with PAX7-labeled satellite cells, with enhanced expression in SKM sections from an 89 yrs old compared to a 27 yrs old. We hypothesized that the SKM aging process might induce compensatory upregulation of INSR and re-expression of INSU, which might be beneficial in early embryogenesis and have deleterious effects on proliferative and myogenic satellite cells with advanced age.
    Keywords:  INSR; insulin; isoforms; satellite cells; skeletal muscle
    DOI:  https://doi.org/10.3390/cells13221903
  20. FASEB J. 2024 Nov 30. 38(22): e70185
      Skeletal muscle activation using optogenetics has emerged as a promising technique for inducing noninvasive muscle contraction and assessing muscle function both in vivo and in vitro. Transgenic mice overexpressing the optogenetic fusion protein, Channelrhodopsin 2-EYFP (ChR2-EYFP) in skeletal muscle are widely used; however, overexpression of fluorescent proteins can negatively impact the functionality of activable tissues. In this study, we characterized the contractile properties of ChR2-EYFP skeletal muscle and introduced the ChR2-only mouse model that expresses light-responsive ChR2 without the fluorescent EYFP in their skeletal muscles. We found a significant reduction in the contractile ability of ChR2-EYFP muscles compared with ChR2-only and WT mice, observed under both electrical and optogenetic stimulation paradigms. Bulk RNAseq identified the downregulation of genes associated with transmembrane transport and metabolism in ChR2-EYFP muscle, while the ChR2-only muscle did not demonstrate any notable deviations from WT muscle. The RNAseq results were further corroborated by a reduced protein-level expression of ion channel-related HCN2 in ChR2-EYFP muscles and gluconeogenesis-modulating FBP2 in both ChR2-EYFP and ChR2-only muscles. Overall, this study reveals an intrinsic skeletal dysfunction in the widely used ChR2-EYFP mice model and underscores the importance of considering alternative optogenetic models, such as the ChR2-only, for future research in skeletal muscle optogenetics.
    Keywords:  Channelrhodopsin‐2; function; optogenetics; skeletal muscle; structure
    DOI:  https://doi.org/10.1096/fj.202401664RR
  21. FASEB J. 2024 Dec 15. 38(23): e70199
      Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK. We treated male and female HSALR mice for 1 and 4 weeks with a daily injection of the allosteric activator MK-8722, the AMP mimetic AICAR, or vehicle. Our results show that 1 and 4 weeks of treatment with MK-8722 improves alternative splicing toward wild-type levels in male and female HSALR muscle. However, the effects of MK-8722 were more modest compared to AICAR. In contrast, 4 weeks of treatment with MK-8722 improved muscle histology to a greater extent than AICAR. As expected with AMPK activation, 4 weeks of treatment with MK-8722 and AICAR promoted the expression of slower, more oxidative fibers. Finally, acute injections of MK-8722 and AICAR triggered the rapid and transient increase in phospho-AMPK in muscle. However, the peak of AMPK phosphorylation was lower with MK-8722 compared to AICAR, thereby explaining the more modest effects of AMPK allosteric activation. Altogether, our data demonstrate that chronic activation of AMPK with specific pharmacological activators is beneficial for the DM1 muscle. They further indicate that at least a portion of the beneficial effects seen following the administration of these drugs occurs through AMPK.
    Keywords:  AICAR; AMPK; MK‐8722; ZLN‐024; allosteric activator; alternative splicing; myotonic dystrophy type 1; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202401145RR
  22. Front Physiol. 2024 ;15 1477976
      In Duchenne muscular dystrophy (DMD), diaphragm muscle dysfunction results in respiratory insufficiency which is a leading cause of death in patients. Mutations to the dystrophin gene result in myocyte membrane instability, contributing to the structural deterioration of the diaphragm muscle tissues. With previous works suggesting the importance of lipin1 for maintaining skeletal muscle membrane integrity, we explored the roles of lipin1 in the dystrophic diaphragm. We found that the protein expression levels of lipin1 were reduced by 60% in the dystrophic diaphragm. While further knockdown of lipin1 in the dystrophic diaphragm leads to increased necroptosis, restoration of lipin1 in the dystrophic diaphragm results in reduced inflammation and fibrosis, decreased myofiber death, and improved respiratory function. Our results demonstrated that lipin1 restoration improved respiratory function by enhancing membrane integrity and suggested that lipin1 could be a potential therapeutic target for preventing respiratory insufficiency and respiratory failure in DMD. Continued investigation is required to better understand the mechanisms behind these findings, and to determine the role of lipin1 in maintaining muscle membrane stability.
    Keywords:  DMD; diaphragm; dystrophin; lipin1; membrane integrity; muscular dystrophy; skeletal muscle; therapeutic target
    DOI:  https://doi.org/10.3389/fphys.2024.1477976
  23. Int J Mol Sci. 2024 Nov 19. pii: 12416. [Epub ahead of print]25(22):
      Exercise is a recognized non-pharmacological treatment for improving glucose homeostasis in type 2 diabetes (T2DM), with resistance exercise (RE) showing promising results. However, the mechanism of RE improving T2DM has not been clarified. This study aims to investigate the effects of RE on glucose and lipid metabolism, insulin signaling, and mitochondrial function in T2DM mice, with a focus on the regulatory role of miR-30d-5p. Our results confirmed that RE significantly improved fasting blood glucose, IPGTT, and ITT in T2DM mice. Enhanced expression of IRS-1, p-PI3K, and p-Akt indicated improved insulin signaling. RE improved glycolipid metabolism, as well as mitochondrial biogenesis and dynamics in skeletal muscle of T2DM mice. We also found that miR-30d-5p was upregulated in T2DM, and was downregulated after RE. Additionally, in vitro, over-expression of miR-30d-5p significantly increased lipid deposition, and reduced glucose uptake and mitochondrial biogenesis. These observations were reversed after transfection with the miR-30d-5p inhibitor. Mechanistically, miR-30d-5p regulates glycolipid metabolism in skeletal muscle by directly targeting SIRT1, which affects the expression of PGC-1α, thereby influencing mitochondrial function and glycolipid metabolism. Taken together, RE effectively improves glucose and lipid metabolism and mitochondrial function in T2DM mice, partly through regulating the miR-30d-5p/SIRT1/PGC-1α axis. miR-30d-5p could serve as a potential therapeutic target for T2DM management.
    Keywords:  T2DM; insulin resistance; miRNAs; resistance exercise; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms252212416
  24. Cells. 2024 Nov 06. pii: 1829. [Epub ahead of print]13(22):
      Store-operated Ca2+ entry (SOCE) controls Ca2+ homeostasis and mediates multiple Ca2+-dependent signaling pathways and cellular processes. It relies on the concerted activity of the reticular Ca2+ sensor STIM1 and the plasma membrane Ca2+ channel ORAI1. STIM1 and ORAI1 gain-of-function (GoF) mutations induce SOCE overactivity and excessive Ca2+ influx, leading to tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and a variable occurrence of multi-systemic anomalies affecting spleen, skin, and platelets. To date, different STIM1 mouse models exist, but only a single ORAI1 mouse model with muscle-specific TAM/STRMK phenotype has been described, precluding a comparative analysis of the physiopathology in all affected tissues. Here, we generated and characterized mice harboring a prevalent ORAI1 TAM/STRMK mutation and we provide phenotypic, physiological, biochemical, and functional data. Examination of Orai1V109M/+ mice revealed smaller size, spleen enlargement, reduced muscle force, and decreased platelet numbers. Morphological analyses of muscle sections evidenced the presence of tubular aggregates, the histopathological hallmark on biopsies from TAM/STRMK patients absent in all reported STIM1 models. Overall, Orai1V109M/+ mice reliably recapitulate the human disorder and highlight the primary physiological defects caused by ORAI1 gain-of-function mutations. They also provide the possibility to investigate the formation of tubular aggregates and to develop a common therapy for different TAM/STRMK forms.
    Keywords:  ORAI1; SOCE; STIM1; Stormorken syndrome; calcium; myopathy
    DOI:  https://doi.org/10.3390/cells13221829
  25. Endocr J. 2024 Nov 22.
      Androgen is widely acknowledged to regulate skeletal muscle mass. However, the specific mechanism driving muscle atrophy resulting from androgen deficiency remains elusive. Systemic androgen receptor knockout (ARKO) mice exhibit reduction in both muscle strength and muscle mass while skeletal muscle fiber specific ARKO mice have decreased muscle strength without affecting skeletal muscle mass in the limbs. Therefore, androgens may indirectly regulate skeletal muscle mass through effects on non-myofibers. Considering this, our investigation focused on blood fluid factors that might play a role in the regulation of skeletal muscle mass under the influence of androgens. Using a male mouse model of sham, orchidectomy and DHT replacement, mass spectrometry for serum samples of each group identified epidermal growth factor receptor (EGFR) as a candidate protein involving the regulation of skeletal muscle mass affected by androgens. Egfr expression in both liver and epididymal white adipose tissue correlated with androgen levels. Furthermore, Egfr expression in these tissues was predominantly elevated in male compared to female mice. Interestingly, male mice exhibited significantly elevated serum EGFR concentrations compared to their female counterparts, suggesting a connection with androgen levels. Treatment of EGFR to C2C12 cells promoted phosphorylation of AKT and its downstream S6K, and enhanced the protein synthesis in vitro. Furthermore, the administration of EGFR to female mice revealed a potential role in promoting an increase in skeletal muscle mass. These findings collectively enhance our understanding of the complex interplay among androgens, EGFR, and the regulation of skeletal muscle mass.
    Keywords:  Akt; Androgen; Androgen receptor (AR); Epidermal growth factor receptor (EGFR); Skeletal muscle
    DOI:  https://doi.org/10.1507/endocrj.EJ24-0410
  26. Sci Transl Med. 2024 Nov 27. 16(775): eadp5730
      TAR DNA binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous systems of some patients with neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy. TDP-43 aggregates from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis, and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding-competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with sporadic inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), and ALS, we found that TDP-43 seeding capacity was specific to IBM. TDP-43 seeding capacity anticorrelated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.
    DOI:  https://doi.org/10.1126/scitranslmed.adp5730
  27. Am J Physiol Endocrinol Metab. 2024 Nov 28.
      AMP-activated protein kinase (AMPK) is an energy sensing serine/threonine kinase involved in metabolic regulation. It is phosphorylated by the upstream liver kinase B1 (LKB1) or calcium/calmodulin-dependent kinase kinase 2 (CaMKKβ). In cultured cells, AMPK activation correlates with LKB1 activity. The phosphorylation activates AMPK, shifting metabolism towards catabolism and promoting mitogenesis. In muscles, inactivity reduces AMPK activation, shifting the phenotype of oxidative muscles towards a more glycolytic profile. Here, we compared the basal level of AMPK activation in glycolytic and oxidative muscles, and whether this relates to LKB1 or CaMKKβ. Using Western blotting, we assessed AMPK expression and phosphorylation in soleus, gastrocnemius, extensor digitorum longus (EDL) and heart from C57BL6J mice. We also assessed LKB1 and CaMKKβ expression, and CaMKKβ activity in tissue homogenates. AMPK activation was higher in oxidative (soleus and heart) than glycolytic muscles (gastrocnemius and EDL). This correlated with AMPK α1-isoform expression, but not LKB1 and CaMKKβ. LKB1 expression was sex dependent and lower in male than female muscles. CaMKKβ expression was very low in skeletal muscles and did not phosphorylate AMPK in muscle lysates. The higher AMPK activation in oxidative muscles is in line with the fact that activated AMPK maintains an oxidative phenotype. However, this could not be explained by LKB1 and CaMKKβ. These results suggest that the regulation of AMPK activation is more complex in muscle than in cultured cells. As AMPK has been proposed as a therapeutic target for several diseases, future research should consider AMPK isoform expression and localization, and energetic compartmentalization.
    Keywords:  AMPK; CaMKKβ; Glycolytic muscle; LKB1; Oxidative muscle
    DOI:  https://doi.org/10.1152/ajpendo.00261.2024
  28. J Cell Mol Med. 2024 Nov;28(22): e70136
      Interleukin-15 (IL-15), a pro-inflammatory cytokine, is produced mainly by skeletal muscle cells, macrophages and epithelial cells. Recent research has demonstrated that IL-15 is closely related to the functions of bone and skeletal muscle in the locomotor system. There is growing evidence that exercise, an important means to regulate the immune and locomotor systems, influences IL-15 content in various tissues, thereby indirectly affecting the function of bones and muscles. Furthermore, the form, intensity, and duration of exercise determine the degree of change in IL-15 and downstream effects. This paper reviews the structure, synthesis and secretion of IL-15, the role of IL-15 in regulating the metabolism of bone tissue cells and myofibers through binding to the IL-15 receptor-α (IL-15Rα), and the response of IL-15 to different types of exercise. This review provides a reference for further analyses of the role and mechanism of action of IL-15 in the regulation of metabolism during exercise.
    Keywords:  bone; exercise; interleukin‐15; locomotor system; metabolism; muscle; training
    DOI:  https://doi.org/10.1111/jcmm.70136
  29. Nat Rev Endocrinol. 2024 Nov 27.
      This Review focuses on currently available literature describing sex differences in skeletal muscle metabolism in humans, as well as highlighting current research gaps within the field. These discussions serve as a call for action to address the current lack of sufficient sex-balanced studies in skeletal muscle research, and the resulting limitations in understanding sex-specific physiological and pathophysiological responses. Although the participation of women in studies has increased, parity between the sexes remains elusive, affecting the validity of conclusions drawn from studies with limited numbers of participants. Changes in skeletal muscle metabolism contribute to the development of metabolic disease (such as type 2 diabetes mellitus), and maintenance of skeletal muscle mass is a key component for health and the ability to maintain an independent life during ageing. Exercise is an important factor in maintaining skeletal muscle health and insulin sensitivity, and offers promise for both prevention and treatment of metabolic disease. With the increased realization of the promise of precision medicine comes the need to increase patient stratification and improve the understanding of responses in different populations. In this context, a better understanding of sex-dependent differences in skeletal muscle metabolism is essential.
    DOI:  https://doi.org/10.1038/s41574-024-01058-9
  30. bioRxiv. 2024 Nov 15. pii: 2024.11.13.623431. [Epub ahead of print]
       Objective: Glucagon-like peptide 1 receptor agonists (e.g. semaglutide) potently induce weight loss and thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency.
    Methods: C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rate of ATP production and O 2 consumption were measured by a high-resolution respirometry and fluorometry to determine OXPHOS efficiency in skeletal muscle at these 2 timepoints.
    Results: Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O 2 consumed (P/O) in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (Lyrm7 and Ttc1, p <0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits.
    Conclusions: These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.
    DOI:  https://doi.org/10.1101/2024.11.13.623431
  31. Nat Commun. 2024 Nov 23. 15(1): 10172
      Cardiopharyngeal mesoderm contributes to the formation of the heart and head muscles. However, the mechanisms governing cardiopharyngeal mesoderm specification remain unclear. Here, we reproduce cardiopharyngeal mesoderm specification towards cardiac and skeletal muscle lineages with gastruloids from mouse embryonic stem cells. By conducting a comprehensive temporal analysis of cardiopharyngeal mesoderm development and differentiation in gastruloids compared to mouse embryos, we present the evidence for skeletal myogenesis in gastruloids. We identify different subpopulations of cardiomyocytes and skeletal muscles, the latter of which most likely correspond to different states of myogenesis with "head-like" and "trunk-like" skeletal myoblasts. In this work, we unveil the potential of gastruloids to undergo specification into both cardiac and skeletal muscle lineages, allowing the investigation of the mechanisms of cardiopharyngeal mesoderm differentiation in development and how this could be affected in congenital diseases.
    DOI:  https://doi.org/10.1038/s41467-024-54466-w
  32. Int J Mol Sci. 2024 Nov 05. pii: 11869. [Epub ahead of print]25(22):
      Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by disruptions in the dystrophin gene. This study aims to investigate potential a therapeutic approach using genetically modified human iPS-derived mesoangioblast-like cells (HIDEMs) in mdx mouse model. This study utilizes patient-specific myoblasts reprogrammed to human induced pluripotent stem cells (iPSCs) and then differentiated into HIDEMs. Lentiviral vectors carrying microdystrophin sequences have been employed to deliver the genetic construct to express a shortened, functional dystrophin protein in HIDEMs. The study indicated significant changes within redox potential between healthy and pathological HIDEM cells derived from DMD patients studied by catalase and superoxide dismutase activities. Microdystrophin expressing HIDEMs also improved expression of genes involved in STARS (striated muscle activator of Rho signaling) pathway albeit in selective DMD patients (with mild phenotype). Although in vivo observations did not bring progress in the mobility of mdx mice with HIDEMs, microdystrophin interventions this may argue against "treadmill test" as suitable for assessment of mdx mice recovery. Low-level signaling of the Rho pathway and inflammation-related factors in DMD myogenic cells can also contribute to the lack of success in a functional study. Overall, this research contributes to the understanding of DMD pathogenesis and provides insights into potential novel therapeutic strategy, highlighting the importance of personalized gene therapy.
    Keywords:  Duchenne Muscular Dystrophy; gene therapy; mdx mice; microdystrophin; muscular dystrophy
    DOI:  https://doi.org/10.3390/ijms252211869
  33. Physiol Rep. 2024 Dec;12(23): e70140
      Insufficient physical activity is associated with increased relative risk of cardiometabolic disease and is an independent risk factor for mortality. Experimentally reducing physical activity rapidly induces insulin resistance, impairs glucose handling, and drives metabolic inflexibility. These adaptations manifest during the early stages of physical inactivity, even when energy balance is maintained, suggesting that inactivity-mediated metabolic reprogramming is an early event that precedes changes in body composition. To identify mechanisms that promote metabolic adaptations associated with physical inactivity, we developed a mouse model of physical activity reduction that permits the study of inactivity in animals prior to the onset of overt changes in body composition. Adult mice were randomized into three groups: an inactive control group (standard rodent housing), an active control group (treadmill running 5 d/week for 6-weeks), and an activity reduction group (treadmill running for 4-weeks, followed by 2-weeks of inactivity). Transcriptional profiling of gastrocnemius muscle identified seven transcripts uniquely altered by physical activity reduction compared to the inactive and active control groups. Most identified transcripts had reported functions linked to bioenergetic adaptation. Future studies will provide deeper characterization of the function(s) of each the identified transcripts while also determining how inactivity affects transcriptional regulation in other tissues.
    Keywords:  physical activity reduction; physical inactivity; skeletal muscle metabolism; skeletal muscle transcriptome
    DOI:  https://doi.org/10.14814/phy2.70140
  34. Antioxidants (Basel). 2024 Nov 16. pii: 1406. [Epub ahead of print]13(11):
      Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic de-repression of the double homeobox 4 (DUX4) gene, leading to asymmetric muscle weakness and atrophy that begins in the facial and scapular muscles and progresses to the lower limbs. This incurable condition can severely impair muscle function, ultimately resulting in a loss of ambulation. A thorough analysis of molecular factors associated with the varying degrees of muscle impairment in FSHD is still lacking. This study investigates the molecular mechanisms and biomarkers in the biceps brachii of FSHD patients, classified according to the FSHD clinical score, the A-B-C-D classification scheme, and global proteomic variation. Our findings reveal distinct metabolic signatures and compensatory responses in patients. In severe cases, we observe pronounced metabolic dysfunction, marked by dysregulated glycolysis, activation of the reductive pentose phosphate pathway (PPP), a shift toward a reductive TCA cycle, suppression of oxidative phosphorylation, and an overproduction of antioxidants that is not matched by an increase in the redox cofactors needed for their function. This imbalance culminates in reductive stress, exacerbating muscle wasting and inflammation. In contrast, mild cases show metabolic adaptations that mitigate stress by activating polyols and the oxidative PPP, preserving partial energy flow through the oxidative TCA cycle, which supports mitochondrial function and energy balance. Furthermore, activation of the hexosamine biosynthetic pathway promotes autophagy, protecting muscle cells from apoptosis. In conclusion, our proteomic data indicate that specific metabolic alterations characterize both mild and severe FSHD patients. Molecules identified in mild cases may represent potential diagnostic and therapeutic targets for FSHD.
    Keywords:  facioscapulohumeral muscular dystrophy; hexosamine biosynthetic pathway; metabolic rewiring; proteomics; redox cofactors
    DOI:  https://doi.org/10.3390/antiox13111406
  35. Int J Mol Sci. 2024 Nov 06. pii: 11936. [Epub ahead of print]25(22):
      Ubiquitin-specific protease 2 (USP2) maintains mitochondrial integrity in culture myoblasts. In this study, we investigated the molecular mechanisms underlying the protective role of USP2 in mitochondria. The knockout (KO) of the Usp2 gene or the chemical inhibition of USP2 induced a robust accumulation of mitochondrial reactive oxygen species (ROS), accompanied by defects in mitochondrial membrane potential, in C2C12 myoblasts. ROS removal by N-acetyl-L-cysteine restored the mitochondrial dysfunction induced by USP2 deficiency. Comprehensive RT-qPCR screening and following protein analysis indicated that both the genetic and chemical inhibition of USP2 elicited a decrease in uncoupling protein 2 (UCP2) at mRNA and protein levels. Accordingly, the introduction of a Ucp2-expressing construct effectively recovered the mitochondrial membrane potential, entailing an increment in the intracellular ATP level in Usp2KO C2C12 cells. In contrast, USP2 deficiency also decreased peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) protein in C2C12 cells, while it upregulated Ppargc1a mRNA. Overexpression studies indicated that USP2 potentially stabilizes PGC1α in an isopeptidase-dependent manner. Given that PGC1α is an inducer of UCP2 in C2C12 cells, USP2 might ameliorate mitochondrial ROS by maintaining the PGC1α-UCP2 axis in myoblasts.
    Keywords:  PGC1α; ROS; mitochondria; myoblasts; ubiquitin-specific protease 2; uncoupling protein 2
    DOI:  https://doi.org/10.3390/ijms252211936