bims-moremu 2024-12-29 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–12–29
27 papers selected by
Anna Vainshtein, Craft Science Inc.

Intrinsic Muscle Stem Cell Dysfunction Contributes to Impaired Regeneration in the mdx Mouse.
Succinate Regulates Exercise-Induced Muscle Remodelling by Boosting Satellite Cell Differentiation Through Succinate Receptor 1.
PRR14 mediates mechanotransduction and regulates myofiber identity via MEF2C in skeletal muscle.
Mll4 in skeletal muscle fibers maintains muscle stem cells.
Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
What are the potential mechanisms of fatigue-induced skeletal muscle hypertrophy with low-load resistance exercise training?
Molecular pathways involved in the control of contractile and metabolic properties of skeletal muscle fibers as potential therapeutic targets for Duchenne muscular dystrophy.
Aerobic Training Alleviates Muscle Atrophy by Promoting the Proliferation of Skeletal Muscle Satellite Cells in Myotonic Dystrophy Type 1 by Inhibiting Glycolysis via the Upregulation of MBNL1.
CSF1-R inhibition attenuates posttraumatic osteoarthritis and quadriceps atrophy following ligament injury.
Chaperone Proteins: The Rising Players in Muscle Atrophy.
Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSCs-derived myogenic progenitor cells.
Syntaxin 4-enhanced plasma membrane repair isindependent of dysferlin in skeletal muscle.
Senescent myoblasts exhibit an altered exometabolome that is linked to senescence-associated secretory phenotype (SASP) signalling.
The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.
Aerobic exercise timing affects mitochondrial dynamics and insulin resistance by regulating the circadian clock protein expression and NAD+-SIRT1-PPARα-MFN2 pathway in the skeletal muscle of high-fat-diet-induced diabetes mice.
Reduced voltage-activated Ca2+ release flux in muscle fibers from a rat model of Duchenne dystrophy.
Alternative Splicing Landscape in Mouse Skeletal Muscle and Adipose Tissue: Effects of Intermittent Fasting and Exercise.
Disrupted methionine cycle triggers muscle atrophy in cancer cachexia through epigenetic regulation of REDD1.
Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.
Protective role of Angiogenin in muscle regeneration in amyotrophic lateral sclerosis: Diagnostic and therapeutic implications.
An immunohistochemical evaluation of fast twitch muscle formation induced by repeated administration of flavan 3-ols in mice.
Circular RNAs and host genes act synergistically in regulating cellular processes and functions in skeletal myogenesis.
Comparative lipidomic and metabolomic profiling of mdx and severe mdx-apolipoprotein e-null mice.
Repeated hyperbaric oxygen exposure accelerates fatigue and impairs SR-calcium release in mice.
Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.
Muscle mass, muscle strength and the renin-angiotensin system.
Proteomics and machine learning: Leveraging domain knowledge for feature selection in a skeletal muscle tissue meta-analysis.

J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13682

Intrinsic Muscle Stem Cell Dysfunction Contributes to Impaired Regeneration in the mdx Mouse.

Marie E Esper, Caroline E Brun, Alexander Y T Lin, Peter Feige, Marie J Catenacci, Marie-Claude Sincennes, Morten Ritso, Michael A Rudnicki.

   BACKGROUND: Duchenne muscular dystrophy (DMD) is a devastating disease characterized by progressive muscle wasting that leads to diminished lifespan. In addition to the inherent weakness of dystrophin-deficient muscle, the dysfunction of resident muscle stem cells (MuSC) significantly contributes to disease progression.
METHODS: Using the mdx mouse model of DMD, we performed an in-depth characterization of disease progression and MuSC function in dystrophin-deficient skeletal muscle using immunohistology, isometric force measurements, transcriptomic analysis and transplantation assays. We examined the architectural and functional changes in mdx skeletal muscle from 13 and 52 weeks of age and following acute cardiotoxin (CTX) injury. We also studied MuSC dynamics and function under homeostatic conditions, during regeneration post-acute injury, and following engraftment using a combination of histological and transcriptomic analyses.
RESULTS: Dystrophin-deficient skeletal muscle undergoes progressive changes with age and delayed regeneration in response to acute injury. Muscle hypertrophy, deposition of collagen and an increase in small myofibres occur with age in the tibialis anterior (TA) and diaphragm muscles in mdx mice. Dystrophic mdx mouse TA muscles become hypertrophic with age, whereas diaphragm atrophy is evident in 1-year-old mdx mice. Maximum tetanic force is comparable between genotypes in the TA, but maximum specific force is reduced by up to 38% between 13 and 52 weeks in the mdx mouse. Following acute injury, myofibre hyperplasia and hypotrophy and delayed recovery of maximum tetanic force occur in the mdx TA. We also find defective MuSC polarity and reduced numbers of myocytes in mdx muscle following acute injury. We observed a 50% and 30% decrease in PAX7+ and MYOG+ cells, respectively, at 5 days post CTX injury (5 dpi) in the mdx TA. A similar decrease in mdx progenitor cell proportion is observed by single cell RNA sequencing of myogenic cells at 5 dpi. The global expression of commitment-related genes is also reduced at 5 dpi. We find a 46% reduction in polarized PARD3 in mdx MuSCs. Finally, mdx MuSCs exhibit elevated PAX7+ cell engraftment with significantly fewer donor-derived myonuclei in regenerated myofibres.
CONCLUSIONS: Our study provides evidence that dystrophin deficiency in MuSCs and myofibres together contributes to progression of DMD. Ongoing muscle damage stimulates MuSC activation; however, aberrant intrinsic MuSC polarity and stem cell commitment deficits due to the loss of dystrophin impair muscle regeneration. Our study provides in vivo validation that dystrophin-deficient MuSCs undergo fewer asymmetric cell divisions, instead favouring symmetric expansion.

Keywords:   mdx ; Duchenne muscular dystrophy; dystrophin; muscle stem cell; regeneration; satellite cell

DOI:  https://doi.org/10.1002/jcsm.13682
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13670

Succinate Regulates Exercise-Induced Muscle Remodelling by Boosting Satellite Cell Differentiation Through Succinate Receptor 1.

Yifan Shi, Da Zhou, Haoyang Wang, Longchang Huang, Xuejin Gao, Gulisudumu Maitiabula, Li Zhang, Xinying Wang.

   BACKGROUND: Skeletal muscle remodelling can cause clinically important changes in muscle phenotypes. Satellite cells (SCs) myogenic potential underlies the maintenance of muscle plasticity. Accumulating evidence shows the importance of succinate in muscle metabolism and function. However, whether succinate can affect SC function and subsequently coordinate muscle remodelling to exercise remains unexplored.
METHODS: A mouse model of high-intensity interval training (HIIT) was used to investigate the effects of succinate on muscle remodelling and SC function by exercise capacity test and biochemical methods. Mice with succinate receptor 1 (SUCNR1)-specific knockout in SCs were generated as an in vivo model to explore the underlying mechanisms. RNA sequencing of isolated SCs was performed to identify molecular changes responding to succinate-SUCNR1 signalling. The effects of identified key molecules on the myogenic capacity of SCs were investigated using gain- and loss-of-function assays in vitro. To support the translational application, the clinical efficacy of succinate was explored in muscle-wasting mice.
RESULTS: After 21 days of HIIT, mice supplemented with 1.5% succinate exhibited striking gains in grip strength (+0.38 ± 0.04 vs. 0.26 ± 0.03 N, p < 0.001) and endurance (+276.70 ± 55.80 vs. 201.70 ± 45.31 s, p < 0.05), accompanied by enhanced muscle hypertrophy and neuromuscular junction regeneration (p < 0.001). The myogenic capacity of SCs was significantly increased in gastrocnemius muscle of mice supplemented with 1% and 1.5% succinate (+16.48% vs. control, p = 0.008; +47.25% vs. control, p < 0.001, respectively). SUCNR1-specific deletion in SCs abolished the modulatory influence of succinate on muscle adaptation in response to exercise, revealing that SCs respond to succinate-SUCNR1 signalling, thereby facilitating muscle remodelling. SUCNR1 signalling markedly upregulated genes associated with stem cell differentiation and phosphorylation pathways within SCs, of which p38α mitogen-activated protein kinase (MAPK; fold change = 6.7, p < 0.001) and protein kinase C eta (PKCη; fold change = 12.5, p < 0.001) expressions were the most enriched, respectively. Mechanistically, succinate enhanced the myogenic capacity of isolated SCs by activating the SUCNR1-PKCη-p38α MAPK pathway. Finally, succinate promoted SC differentiation (1.5-fold, p < 0.001), ameliorating dexamethasone-induced muscle atrophy in mice (p < 0.001).
CONCLUSIONS: Our findings reveal a novel function of succinate in enhancing SC myogenic capacity via SUCNR1, leading to enhanced muscle adaptation in response to exercise. These findings provide new insights for developing pharmacological strategies to overcome muscle atrophy-related diseases.

Keywords:  PKCη; SUCNR1; muscle remodelling; satellite cells; succinate

DOI:  https://doi.org/10.1002/jcsm.13670
Metabolism. 2024 Dec 18. pii: S0026-0495(24)00337-8. [Epub ahead of print]164 156109

PRR14 mediates mechanotransduction and regulates myofiber identity via MEF2C in skeletal muscle.

Mei Yang, Jiajie Wang, Zhongyue Liu, Zhihong Li.

  Skeletal muscle is a crucial tissue for physical activity and energy metabolism. Muscle atrophy, characterized by the loss of muscle mass and strength, contributes to adverse outcomes among individuals. This study elucidated the involvement of the nuclear lamina component PRR14 in transmitting mechanical signals and mediating the impact of exercise on skeletal muscle. The expression of PRR14 demonstrated a positive correlation with exercise, while a decline in adult skeletal muscle is evident in disuse muscle conditions. Genetically, multiple single nucleotide polymorphisms (SNPs) within PRR14's genomic locus were linked with muscle mass and function. Specific knockout (KO) of skeletal muscle Prr14 in mice lead to muscle atrophy, validating the genetic association. By employing biochemical analysis and high-throughput sequencing techniques, including transcriptome profile and epigenome investigations such as Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and Transposase-Accessible Chromatin sequencing (ATAC-seq), we discovered that PRR14's deficiency altered chromatin structure, regulated MEF2C's activity, and disrupted myofiber identity maintenance, ultimately causing muscle atrophy. Our finding highlights the crucial role of PRR14 in mechanotransduction and epigenetic regulation, offering new therapeutic avenues for skeletal muscle pathologies related to these mechanisms.

Keywords:  MEF2C; Mechanotransduction; Muscle atrophy; Myofiber identity; Nuclear lamina; PRR14

DOI:  https://doi.org/10.1016/j.metabol.2024.156109
Skelet Muscle. 2024 Dec 23. 14(1): 35

Mll4 in skeletal muscle fibers maintains muscle stem cells.

Yea-Eun Kim, Sang-Hyeon Hann, Young-Woo Jo, Kyusang Yoo, Ji-Hoon Kim, Jae W Lee, Young-Yun Kong.

   BACKGROUND: Muscle stem cells (MuSCs) undergo numerous state transitions throughout life, which are critical for supporting normal muscle growth and regeneration. Epigenetic modifications in skeletal muscle play a significant role in influencing the niche and cellular states of MuSCs. Mixed-lineage leukemia 4 (Mll4) is a histone methyltransferase critical for activating the transcription of various target genes and is highly expressed in skeletal muscle. This raises the question of whether Mll4 has a regulatory function in modulating the state transitions of MuSCs, warranting further investigation.
METHODS: To assess if myofiber-expressed Mll4, a histone methyltransferase, contributes to the maintenance of MuSCs, we crossed MCKCre/+ or HSAMerCreMer/+ mice to Mll4f/f mice to generate myofiber-specific Mll4-deleted mice. Investigations were conducted using 8-week-old and 4-week-old MCKCre/+;Mll4f/f mice, and adult HSAMerCreMer/+;Mll4f/f mice between the ages of 3 months and 6 months.
RESULTS: During postnatal myogenesis, Mll4 deleted muscles were observed with increased number of cycling MuSCs that proceeded to a differentiation state, leading to MuSC deprivation. This phenomenon occurred independently of gender. When Mll4 was ablated in adult muscles using the inducible method, adult MuSCs lost their quiescence and differentiated into myoblasts, also causing the depletion of MuSCs. Such roles of Mll4 in myofibers coincided with decreased expression levels of distinct Notch ligands: Jag1 and Dll1 in pubertal and Jag2 and Dll4 in adult muscles.
CONCLUSIONS: Our study suggests that Mll4 is crucial for maintaining MuSCs in both pubertal and adult muscles, which may be accomplished through the modulation of distinct Notch ligand expressions in myofibers. These findings offer new insights into the role of myofiber-expressed Mll4 as a master regulator of MuSCs, highlighting its significance not only in developmental myogenesis but also in adult muscle, irrespective of sex.

Keywords:  Exercise; Muscle stem cells; Myeloid/lymphoid or mixed-lineage leukemia 4 (Mll4); Myofiber; Notch signaling; Skeletal muscle

DOI:  https://doi.org/10.1186/s13395-024-00369-9
Free Radic Biol Med. 2024 Dec 18. pii: S0891-5849(24)01147-X. [Epub ahead of print]227 619-628

Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.

Yiwei Feng, Zhijian Rao, Xu Tian, Yi Hu, Liantian Yue, Yifan Meng, Qiuling Zhong, Wei Chen, Wenlong Xu, Haoran Li, Yingjia Hu, Rengfei Shi.

  The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and endurance exercise adaptations is unknown. Here, we tested indices such as maximal oxygen uptake and serum MOTS-c levels in marathon runners and sedentary subjects. In addition, we tested aerobic exercise capacity, skeletal muscle mitochondrial respiration rate, and serum MOTS-c levels in mice subjected to long-term endurance training groups and sedentary groups. Our results indicated a close association between serum MOTS-c levels and aerobic exercise capacity. Circulating MOTS-c levels are expected to be an important indicator for predicting aerobic exercise capacity and assessing body fat status, endurance training load, and physical function. More importantly, we found that endurance training may enhance the mitochondrial respiratory function of skeletal muscle by promoting the secretion of MOTS-c and activating the AMPK/PGC-1α pathway.

Keywords:  Exercise; Mitochondria; Mitochondrial-derived peptides; Skeletal muscle; The mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-C)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.038
Am J Physiol Cell Physiol. 2024 Dec 26.

What are the potential mechanisms of fatigue-induced skeletal muscle hypertrophy with low-load resistance exercise training?

Luke D Flewwelling, Sarkis J Hannaian, Victor Cao, Thomas Chaillou, Tyler A Churchward-Venne, Arthur J Cheng.

  High-load resistance exercise (>60% of 1-repetition maximum) is a well-known stimulus to enhance skeletal muscle hypertrophy with chronic training. However, studies have intriguingly shown that low-load resistance exercise training (RET) (≤60% of 1-repetition maximum) can lead to similar increases in skeletal muscle hypertrophy as compared to high-load RET. This has raised questions about the underlying mechanisms for eliciting the hypertrophic response with low-load RET. A key characteristic of low-load RET is performing resistance exercise to, or close to, task failure, thereby inducing muscle fatigue. The primary aim of this evidence-based narrative review is to explore whether muscle fatigue may act as an indirect or direct mechanism contributing to skeletal muscle hypertrophy during low-load RET. It has been proposed that muscle fatigue could indirectly stimulate muscle hypertrophy through increased muscle fibre recruitment, mechanical tension, ultrastructural muscle damage, the secretion of anabolic hormones, and/or alterations in the expression of specific proteins involved in muscle mass regulation (e.g., myostatin). Alternatively, it has been proposed that fatigue could directly stimulate muscle hypertrophy through the accumulation of metabolic by-products (e.g., lactate), and/or inflammation and oxidative stress. This review summarizes the existing literature eluding to the role of muscle fatigue as a stimulus for low-load RET-induced muscle hypertrophy and provides suggested avenues for future research to elucidate how muscle fatigue could mediate skeletal muscle hypertrophy.

Keywords:  Strength training; hypertrophy; low-load; muscle failure; skeletal muscle growth

DOI:  https://doi.org/10.1152/ajpcell.00266.2024
Front Physiol. 2024 ;15 1496870

Molecular pathways involved in the control of contractile and metabolic properties of skeletal muscle fibers as potential therapeutic targets for Duchenne muscular dystrophy.

Agnese Bonato, Giada Raparelli, Maurizia Caruso.

  Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, a subsarcolemmal protein whose absence results in increased susceptibility of the muscle fiber membrane to contraction-induced injury. This results in increased calcium influx, oxidative stress, and mitochondrial dysfunction, leading to chronic inflammation, myofiber degeneration, and reduced muscle regenerative capacity. Fast glycolytic muscle fibers have been shown to be more vulnerable to mechanical stress than slow oxidative fibers in both DMD patients and DMD mouse models. Therefore, remodeling skeletal muscle toward a slower, more oxidative phenotype may represent a relevant therapeutic approach to protect dystrophic muscles from deterioration and improve the effectiveness of gene and cell-based therapies. The resistance of slow, oxidative myofibers to DMD pathology is attributed, in part, to their higher expression of Utrophin; there are, however, other characteristics of slow, oxidative fibers that might contribute to their enhanced resistance to injury, including reduced contractile speed, resistance to fatigue, increased capillary density, higher mitochondrial activity, decreased cellular energy requirements. This review focuses on signaling pathways and regulatory factors whose genetic or pharmacologic modulation has been shown to ameliorate the dystrophic pathology in preclinical models of DMD while promoting skeletal muscle fiber transition towards a slower more oxidative phenotype.

Keywords:  duchenne muscular dystrophy; phenotypic modifiers; skeletal muscle fiber types; skeletal muscle metabolism; therapeutic strategies

DOI:  https://doi.org/10.3389/fphys.2024.1496870
Curr Stem Cell Res Ther. 2024 Dec 20.

Aerobic Training Alleviates Muscle Atrophy by Promoting the Proliferation of Skeletal Muscle Satellite Cells in Myotonic Dystrophy Type 1 by Inhibiting Glycolysis via the Upregulation of MBNL1.

Hui-Qi Wang, Min Guo, Jie-Qiong Lu, Lin-Yun Chen, Feng Liang, Peng-Peng Huang, Kai-Yi Song.

   BACKGROUND: Skeletal muscle atrophy in myotonic dystrophy type 1 (DM1) is caused by abnormal skeletal muscle satellite cell (SSC) proliferation due to increased glycolysis, which impairs muscle regeneration. In DM1, RNA foci sequester muscleblind-like protein 1 (MBNL1) in the nucleus, inhibiting its role in regulating SSC proliferation. Aerobic training reduces glycolysis and increases SSC proliferation and muscle fiber volume. This study aimed to investigate whether aerobic training prevents muscle atrophy in DM1 through the regulation of glycolysis via MBNL1.
METHODS: In this study, we used the HSALR transgenic mice (DM1 mice model) to investigate the effects of aerobic training on skeletal muscle atrophy and its molecular mechanisms. HSALR mice were subjected to 4 weeks of aerobic training. After aerobic training, hindlimb grip, and myofiber mean cross-sectional area (CSA) detected by haematoxylin and eosin (HE) staining were performed. In DM1 primary SSCs, cell proliferation was assessed using Pax7 and MyoD immunofluorescence and CCK-8 assays, RNA foci were detected by RNA fluorescence in situ hybridization, and total MBNL1 expression was measured by western blot. We also used lentivirus to knock down MBNL1 in DM1 primary SSCs and performed RNA sequencing and extracellular acidification rate (ECAR). Furthermore, glycolysis detected by ECAR and oxygen consumption rate (OCR) assays were performed in WT, Sedentary, and Training group SSCs. Glycolysis was inhibited with shikonin, a glycolysis inhibitor, and the proliferation of DM1 SSCs was subsequently evaluated. Finally, we engineered an adeno-associated virus specifically targeting MBNL1 to knock down MBNL1 in DM1 mice. Subsequently, we assessed hindlimb grip strength and CSA in vivo, as well as the glycolytic capacity and proliferative capacity of DM1 SSCs in vitro.
RESULTS: Aerobic training increased hindlimb grip strength and the average myofiber CSA in DM1 mice. Additionally, aerobic training reduced RNA foci, upregulated MBNL1, and promoted SSC proliferation. Gene-set enrichment analysis (GSEA) indicated that glycolytic processes were enriched following the knockdown of MBNL1. Furthermore, ECAR showed glycolysis was enhanced after the knockdown of MBNL1. Aerobic training reduced elevated glycolysis in DM1 mice and primary SSCs. Treatment with shikonin promoted DM1 SSC proliferation. However, MBNL1 knockdown was shown to abolish the reduced glycolysis and increased proliferation capability of SSCs due to aerobic training.
CONCLUSION: Taken together, aerobic training suppresses glycolysis in SSCs via the upregulation of MBNL1, thereby enhancing SSC proliferation and alleviating muscle atrophy.

Keywords:  Aerobic training; glycolysis; muscle atrophy; myotonic dystrophy type 1.; skeletal muscle satellite cell

DOI:  https://doi.org/10.2174/011574888X360503241214045130
J Physiol. 2024 Dec 22.

CSF1-R inhibition attenuates posttraumatic osteoarthritis and quadriceps atrophy following ligament injury.

Alexander R Keeble, Nicholas T Thomas, Peyton J Balawender, Camille R Brightwell, Sara Gonzalez-Velez, Madeline G O'Daniel, Caitlin E Conley, Austin V Stone, Darren L Johnson, Brian Noehren, Cale A Jacobs, Christopher S Fry, Allison M Owen.

  Knee osteoarthritis contributes substantially to worldwide disability. Post-traumatic osteoarthritis (PTOA) develops secondary to joint injury, such as ligament rupture, and there is increasing evidence suggesting a key role for inflammation in the aetiology of PTOA and associated functional deficits. Colony stimulating factor 1 receptor (CSF1-R) has been implicated in the pathogenesis of musculoskeletal degeneration following anterior cruciate ligament (ACL) injury. We sought to assess the efficacy of CSF1-R inhibition to mitigate muscle and joint pathology in a mouse model of PTOA. Four-month-old mice were randomized to receive a CSF1-R inhibitor and studied for 7 or 28 days after joint injury. Additionally, we profiled synovial fluid samples for CSF1-R from patients with injury to their ACL. Transcriptomic analysis of quadriceps muscle and articular cartilage in CSF1-R inhibitor-treated animals at 7 days after injury revealed elevated chondrocyte differentiation within articular cartilage and enhanced metabolic and contractile gene expression within skeletal muscle. At 28 days post-injury, CSF1-R inhibition attenuated PTOA severity and mitigated skeletal muscle atrophy. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA. Our findings support an opportunity for CSF1-R targeting to mitigate the severity of PTOA and muscle atrophy after joint injury. KEY POINTS: Posttraumatic osteoarthritis (PTOA) of the knee commonly results from direct injury to the joint, which is characterized by pain, weakness, and disability. Induction of colony stimulating factor one receptor (CSF1-R) is positively associated with knee trauma severity, and the initial acute inflammatory state suppresses muscle recovery and degrades articular cartilage. Skeletal muscle and articular cartilage transcriptomic response following direct joint injury in a murine model of PTOA is rescued by pharmacological inhibition of CSF1-R. CSF1-R inhibition mitigated skeletal muscle atrophy and attenuated PTOA severity and synovitis. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA, offering further evidence for CSF1-R as a therapeutic target across musculoskeletal tissues after injury.

Keywords:  anterior cruciate ligament; cartilage; inflammation; skeletal muscle

DOI:  https://doi.org/10.1113/JP286815
J Cachexia Sarcopenia Muscle. 2024 Dec 20.

Chaperone Proteins: The Rising Players in Muscle Atrophy.

Davide Acquarone, Alessandro Bertero, Mara Brancaccio, Matteo Sorge.

  Despite significant progress in understanding the molecular aetiology of muscle atrophy, there is still a great need for new targets and drugs capable of counteracting muscle wasting. The role of an impaired proteostasis as the underlying causal mechanism of muscle atrophy is a well-established concept. From the earliest work on muscle atrophy and the identification of the first atrogenes, the hyper-activation of the proteolytic systems, such as autophagy and the ubiquitin proteasome system, has been recognized as the major driver of atrophy. However, the role of other key regulators of proteostasis, the chaperone proteins, has been largely overlooked. Chaperone proteins play a pivotal role in protein folding and in preventing the aggregation of misfolded proteins. Indeed, some chaperones, such as αB-crystallin and Hsp25, are involved in compensatory responses aimed at counteracting protein aggregation during sarcopenia. Chaperones also regulate different intracellular signalling pathways crucial for atrogene expression and the control of protein catabolism, such as the AKT and NF-kB pathways, which are regulated by Hsp70 and Hsp90. Furthermore, the downregulation of certain chaperones causes severe muscle wasting per se and experimental strategies aimed at preventing this downregulation have shown promising results in mitigating or reversing muscle atrophy. This highlights the therapeutic potential of targeting chaperones and confirms their crucial anti-atrophic functions. In this review, we summarize the most relevant data showing the modulation and the causative role of chaperone proteins in different types of skeletal muscle atrophies.

Keywords:  cachexia; chaperone proteins; heat shock proteins; muscle atrophy; proteostasis; sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13659
bioRxiv. 2024 Dec 10. pii: 2024.12.09.624203. [Epub ahead of print]

Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSCs-derived myogenic progenitor cells.

Luca Caputo, Cedomir Stamenkovic, Matthew T Tierney, Maria Sofia Falzarano, Rhonda Bassel-Duby, Alessandra Ferlini, Eric N Olson, Pier Lorenzo Puri, Alessandra Sacco.

  Generation of in vitro induced pluripotent cells (hiPSCs)-derived skeletal muscle progenitor cells (SMPCs) holds great promise for regenerative medicine for skeletal muscle wasting diseases, as for example Duchenne Muscular Dystrophy (DMD). Multiple approaches, involving ectopic expression of key regulatory myogenic genes or small molecules cocktails, have been described by different groups to obtain SMPC towards cell-transplantation in vivo as a therapeutic approach to skeletal muscle diseases. However, hiPSCs-derived SMPC generated using transgene-free protocols are usually obtained in a low amount and resemble a more embryonal/fetal stage of differentiation. Here we demonstrate that modulation of the JAK2/STAT3 signaling pathway during an in vitro skeletal muscle differentiation protocol, increases the yield of PAX7+ and CD54+ SMPCs and drive them to a postnatal maturation stage, in both human ES and patient-derived iPSCs. Importantly, upon removal of the inhibition from the cultures, the obtained SMPCs are able to differentiate into multinucleated myotubes in vitro. These findings reveal that modulation of the JAK2/STAT3 signaling pathway is a potential therapeutic avenue to generate SMPCs in vitro with increase potential for cell-therapy approaches.

Keywords:  Duchenne Muscular Dystrophy; STAT3 pathway; hiPSC; myotubes; skeletal muscle progenitor cells

DOI:  https://doi.org/10.1101/2024.12.09.624203
Am J Physiol Cell Physiol. 2024 Dec 26.

Syntaxin 4-enhanced plasma membrane repair isindependent of dysferlin in skeletal muscle.

Hsin-Yu Chen, Daniel E Michele.

  Plasma membrane repair (PMR) restores membrane integrity of cells, preventing cell death in vital organs, and has been studied extensively in skeletal muscle. Dysferlin, a sarcolemmal Ca2+-binding protein, plays a crucial role in PMR in skeletal muscle. Previous studies have suggested that PMR employs membrane trafficking and membrane fusion, similar to neurotransmission. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) mediate membrane fusion in neurotransmission with the help of synaptotagmin, a crucial Ca2+-binding protein. Interestingly, dysferlin shares structural similarity with synaptotagmin and was shown to promote SNARE-mediated membrane fusion in a liposome-based assay. However, whether dysferlin facilitates SNARE-mediated membrane fusion in PMR in muscle cells remains unclear. In this study, we aimed to test if SNARE-mediated PMR requires dysferlin in muscle cells with pharmacological and genetic approaches. TAT-NSF700, which disrupts disassembly of SNARE complexes, was used to disrupt functions of SNAREs in muscle cells. We found that human induced pluripotent stem cells-derived cardiomyocytes (hiPS-CMs) treated with TAT-NSF700 showed a higher loss of membrane integrity after repetitive mechanical strains. Moreover, laser-wounded mouse flexor digitorum brevis (FDB) fibers treated with TAT-NSF700 showed an increased Ca2+ influx, but a decreased FM1-43 uptake, which depends on dynamin-regulated endocytosis as we previously showed in FDB fibers. Importantly, overexpression of STX4-mCitrine or eGFP-SNAP23 decreased Ca2+ influx in laser-wounded FDB fibers. Further, overexpression of STX4-mCitrine also decreased Ca2+ influx in laser-wounded dysferlin-deficient FDB fibers. Overall, these results suggest that disassembly of SNARE complexes is required for efficient PMR, and STX4-enhanced PMR does not require dysferlin in skeletal muscle.

Keywords:  SNAREs; dysferlin; plasma membrane repair; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00507.2024
Am J Physiol Cell Physiol. 2024 Dec 26.

Senescent myoblasts exhibit an altered exometabolome that is linked to senescence-associated secretory phenotype (SASP) signalling.

Michael Kamal, Meera Shanmuganathan, Zachery Kroezen, Sophie Joanisse, Philip Britz-McKibbin, Gianni Parise.

  Cellular senescence has been implicated in the aging-related dysfunction of satellite cells, the resident muscle stem cell population primarily responsible for the repair of muscle fibres. Despite being in a state of permanent cell cycle arrest, these cells remain metabolically active and release an abundance of factors that can have detrimental effects on the cellular microenvironment. This phenomenon is known as the senescence-associated secretory phenotype (SASP), and its metabolic profile is poorly characterized in senescent muscle. In the present investigation, we examined the intracellular and extracellular metabolome of C2C12 myoblasts using a bleomycin-mediated model of DNA damage-induced senescence. We also evaluated the relationship between the senescent metabolic phenotype and SASP signalling through molecular and network-based analyses. Senescent myoblasts exhibited a significantly altered extracellular metabolome (i.e. exometabolome), including increased secretion of several aging-associated metabolites. Four of these metabolites - trimethylamine-N-oxide (TMAO), xanthine, choline, and oleic acid - were selected for individual dose-response experiments to determine if they could drive the senescence phenotype. While most of the tested metabolites did not independently alter senescence markers, oleic acid treatment of healthy myoblasts significantly upregulated the SASP genes Ccl2, Cxcl12, and Il33 (p<0.05). A gene-metabolite interaction network further revealed that oleic acid was one of the most interconnected metabolites to key senescence-associated genes. Notably, oleic acid interacted with several prominent SASP genes, suggesting a potential epigenetic effect between this monounsaturated fatty acid and SASP regulation. In summary, the exometabolome, particularly oleic acid, is implicated in SASP signalling within senescent myoblasts.

Keywords:  SASP; metabolome; myoblast; senescence; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00880.2024
Am J Physiol Endocrinol Metab. 2024 Dec 23.

The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.

Robert G Leija, Jose A Arevalo, Dianna Xing, José Pablo Vázquez-Medina, George A Brooks.

  The Lactate Shuttle concept has revolutionized our understanding and study of metabolism in physiology, biochemistry, metabolism, nutrition, and medicine. Seminal findings of the Mitochondrial Lactate Oxidation Complex (mLOC) elucidated the architectural structure of its components. Here, we report that the mitochondrial pyruvate carrier (mPC) is an additional member of the mLOC in mouse muscle and C2C12 myoblasts and myotubes. Immunoblots, mass spectrometry, and co-immunoprecipitation experiments of mitochondrial preparations revealed abundant amounts of mitochondrial lactate dehydrogenase (mLDH), monocarboxylate transporter (mMCT), basigin (CD147), cytochrome oxidase (COx), and pyruvate carriers 1 and 2 (mPC1 and 2). Additionally, using confocal laser scanning microscopy (CLSM) and in situ proximity ligation, we also demonstrated planar and 3D colocalization of pyruvate and lactate transporters with COx in fixed skeletal muscle sections, myotubes, and C2C12 myoblasts. This work serves as a landmark for configuring the final pathway of carbohydrate oxidation.

Keywords:  Lactate; Lactate Shuttle; Mitochondral Reticulum; Pyruvate; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpendo.00306.2024
J Physiol Biochem. 2024 Dec 24.

Aerobic exercise timing affects mitochondrial dynamics and insulin resistance by regulating the circadian clock protein expression and NAD+-SIRT1-PPARα-MFN2 pathway in the skeletal muscle of high-fat-diet-induced diabetes mice.

Raha Pourabdi, Fereshteh Shahidi, Mohammad Reza Tabandeh, Mojtaba Salehpour.

  The circadian clock regulates mitochondrial function and affects time-dependent metabolic responses to exercise. The present study aimed to determine the effects of aerobic exercise timing at the light-dark phase on the proteins expression of the circadian clock, mitochondrial dynamics, and, NAD+-SIRT1-PPARα axis in skeletal muscle of high-fat diet-induced diabetic mice. In this experimental study, thirty male mice were randomly assigned into two groups based on time: the early light phase, ZT3, and the early dark phase, ZT15, and three groups at each time: (1) Healthy Control (HC), (2) Diabetic Control (DC), and (3) Diabetic + Exercise (DE). Diabetes was induced by 5 weeks of feeding with a high-fat diet and Streptozotocin injection. Following confirmation of diabetes, animals underwent treadmill running at ZT3 and ZT15 for eight-weeks (5 days, 60-80 min, 50-60%Vmax). The expression of proteins of muscle aryl-hydrocarbon receptor nuclear translocator-like-1 (BMAL1), period-2 (PER2), mitofusin-2 (MFN2), dynamin-related proteins-1 (DRP-1), glucose transporter (GLUT4), sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-alpha (PPARα), and nicotinamide adenine dinucleotide (NAD+) level were analyzed in gastrocnemius muscle at both exercise times. The results showed that aerobic exercise at both times reversed the dysregulation of the diabetes-induced skeletal muscle clock by increasing the BMAL1 and PER2 protein levels. Aerobic exercise, especially at ZT15 compared to ZT3, increased GLUT4-mediated glucose uptake, and improved the diabetes-induced imbalance of mitochondrial fusion-fission by a significant increase in MFN2 protein level. Moreover, time-dependent aerobic exercise only at ZT15 increased the SIRT1 and PPARα protein levels and reduced diabetes-induced hyperglycemia. However, the aerobic exercise timing could not restore the attenuation of diabetes-induced NAD+ levels and DRP-1 protein. Our findings demonstrated that the synchronization of aerobic exercise with the circadian rhythm of NAD+-SIRT1 may boost MFN2-mediated mitochondrial fusion by activating the BMAL1-PER2-SIRT1-PPARα axis in the skeletal muscle of diabetic mice and be more effective in facilitating glycemic control and insulin resistance.

Keywords:  Aerobic exercise timing; Circadian molecular clock; Diabetes; Insulin resistance; Mitochondrial dynamics; NAD+/SIRT1; Skeletal muscle

DOI:  https://doi.org/10.1007/s13105-024-01066-3
J Gen Physiol. 2025 Mar 03. pii: e202413588. [Epub ahead of print]157(2):

Reduced voltage-activated Ca2+ release flux in muscle fibers from a rat model of Duchenne dystrophy.

Jonathan Schreiber, Ludivine Rotard, Yves Tourneur, Aude Lafoux, Christine Berthier, Bruno Allard, Corinne Huchet, Vincent Jacquemond.

The potential pathogenic role of disturbed Ca2+ homeostasis in Duchenne muscular dystrophy (DMD) remains a complex, unsettled issue. We used muscle fibers isolated from 3-mo-old DMDmdx rats to further investigate the case. Most DMDmdx fibers exhibited no sign of trophic or morphology distinction as compared with WT fibers and mitochondria and t-tubule membrane networks also showed no stringent discrepancy. Under voltage clamp, values for holding current were similar in the two groups, whereas values for capacitance were larger in DMDmdx fibers, suggestive of enhanced amount of t-tubule membrane. The Ca2+ current density across the channel carried by the EC coupling voltage sensor (CaV1.1) was unchanged. The maximum rate of voltage-activated sarcoplasmic reticulum (SR) Ca2+ release was reduced by 25% in the DMDmdx fibers, with no change in voltage dependency. Imaging resting Ca2+ revealed rare spontaneous local SR Ca2+ release events with no sign of elevated activity in DMDmdx fibers. Under current clamp, DMDmdx fibers generated similar trains of action potentials as WT fibers. Results suggest that reduced peak amplitude of SR Ca2+ release is an inherent feature of this DMD model, likely contributing to muscle weakness. This occurs despite a preserved amount of releasable Ca2+ and with no change in excitability, CaV1.1 channel activity, and SR Ca2+ release at rest. Although we cannot exclude that fibers from the 3-mo-old animals do not yet display a fully developed disease phenotype, results provide limited support for pathomechanistic concepts frequently associated with DMD such as membrane fragility, excessive Ca2+ entry, or enhanced SR Ca2+ leak.

DOI: https://doi.org/10.1085/jgp.202413588
J Nutr Biochem. 2024 Dec 24. pii: S0955-2863(24)00268-7. [Epub ahead of print] 109837

Alternative Splicing Landscape in Mouse Skeletal Muscle and Adipose Tissue: Effects of Intermittent Fasting and Exercise.

Jasmin Gaugel, Markus Jähnert, Alexander Neumann, Florian Heyd, Annette Schürmann, Heike Vogel.

  Alternative splicing contributes to diversify the cellular protein landscape, but aberrant splicing is implicated in many diseases. To which extent mis-splicing contributes to insulin resistance as the causal defect of type 2 diabetes and whether this can be reversed by lifestyle interventions is largely unknown. Therefore, RNA sequencing data from skeletal muscle and adipose tissue of diabetes-susceptible NZO mice treated with or without intermittent fasting and of healthy C57BL/6J mice subjected to exercise were analyzed for alternative splicing differences using Whippet and rMATS. Diet and exercise interventions triggered comparable levels of splicing changes, although the splicing profile of skeletal muscle appeared to be more flexible than that of adipose tissue, with 72-114 differential splicing events in muscle and less than 25 in adipose tissue. Splicing changes induced by time-restricted feeding, alternate-day fasting and exercise were generally mild, with a maximal percent spliced in (PSI) difference of 67%, indicating that alternative splicing plays a rather minor role in lifestyle-induced adaptations of muscle and adipose tissue in mice. However, intron retention contributed to the regulation of gene expression, influencing genes whose expression was directly linked to phenotypic parameters (e.g. Eno2 and Pan2). Alternate-day fasting promoted skipping of exon 7 in Mlxipl (coding for ChREBP), thereby affecting the glucose sensing module of this carbohydrate-responsive transcription factor. Both intermittent fasting and exercise training led to alternative splicing of known diabetes-related GWAS genes (e.g. Abcc8, Ifnar2, Smarcad1), highlighting the potential metabolic relevance of these changes.

Keywords:  Alternative splicing; lifestyle interventions; obesity; skeletal muscle; type 2 diabetes; white adipose tissue

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109837
Cell Metab. 2024 Dec 20. pii: S1550-4131(24)00413-3. [Epub ahead of print]

Disrupted methionine cycle triggers muscle atrophy in cancer cachexia through epigenetic regulation of REDD1.

Kai Lin, Lulu Wei, Ranran Wang, Li Li, Shiyu Song, Fei Wang, Meiwei He, Wenyuan Pu, Jinglin Wang, Junaid Wazir, Wangsen Cao, Xiaozhong Yang, Eckardt Treuter, Rongrong Fan, Yongxiang Wang, Zhiqiang Huang, Hongwei Wang.

  The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAM), a critical supplier for DNA methylation and thereby a modulator of gene expression. Here, we report that the methionine cycle is disrupted in skeletal muscle during cancer cachexia, leading to endoplasmic reticulum stress and DNA hypomethylation-induced expression of the DNA damage inducible transcript 4 (Ddit4) gene, encoding the regulated in development and DNA damage response 1 (REDD1) protein. Targeting DNA methylation by depletion or pharmacological inhibition of DNA methyltransferase 3A (DNMT3A) exacerbates cachexia, while restoring DNMT3A expression or REDD1 knockout alleviates cancer cachexia-induced skeletal muscle atrophy in mice. Methionine supplementation restores DNA methylation of the Ddit4 promoter in a DNMT3A-dependent manner, thereby inhibiting activating transcription factor 4 (ATF4)-mediated Ddit4 transcription. Thus, with the identification of the methionine/SAM-DNMT3A/DNA hypomethylation-Ddit4/REDD1 axis, our study provides molecular insights into an epigenetic mechanism underlying cancer cachexia, and it suggests nutrient supplementation as a promising therapeutic strategy to prevent or reverse cachectic muscle atrophy.

Keywords:  C2C12 myotubes; DNA methylation; DNMT; ER stress; REDD1; cancer cachexia; epigenetic regulation; methionine metabolism; muscle atrophy

DOI:  https://doi.org/10.1016/j.cmet.2024.10.017
Cell Death Discov. 2024 Dec 21. 10(1): 510

Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.

Erica Pranzini, Livio Muccillo, Ilaria Nesi, Alice Santi, Caterina Mancini, Giulia Lori, Massimo Genovese, Tiziano Lottini, Giuseppina Comito, Anna Caselli, Annarosa Arcangeli, Lina Sabatino, Vittorio Colantuoni, Maria Letizia Taddei, Paolo Cirri, Paolo Paoli.

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of body weight occurring in about 80% of cancer patients, frequently representing the leading cause of death. Dietary intervention is emerging as a promising therapeutic strategy to counteract cancer-induced wasting. Serine is the second most-consumed amino acid (AA) by cancer cells and has emerged to be strictly necessary to preserve skeletal muscle structure and functionality. Here, we demonstrate that decreased serine availability during tumor progression promotes myotubes diameter reduction in vitro and induces muscle wasting in in vivo mice models. By investigating the metabolic crosstalk between colorectal cancer cells and muscle cells, we found that incubating myotubes with conditioned media from tumor cells relying on exogenous serine consumption triggers pronounced myotubes diameter reduction. Accordingly, culturing myotubes in a serine-free medium induces fibers width reduction and suppresses the activation of the AKT-mTORC1 pathway with consequent impairment in protein synthesis, increased protein degradation, and enhanced expression of the muscle atrophy-related genes Atrogin1 and MuRF1. In addition, serine-starved conditions affect myoblast differentiation and mitochondrial oxidative metabolism, finally inducing oxidative stress in myotubes. Consistently, serine dietary deprivation strongly strengthens cancer-associated weight loss and muscle atrophy in mice models. These findings uncover serine consumption by tumor cells as a previously undisclosed driver in cancer cachexia, opening new routes for possible therapeutic approaches.

DOI: https://doi.org/10.1038/s41420-024-02271-1
Brain Pathol. 2024 Dec 28. e13328

Protective role of Angiogenin in muscle regeneration in amyotrophic lateral sclerosis: Diagnostic and therapeutic implications.

Paola Fabbrizio, Sharada Baindoor, Cassandra Margotta, Junyi Su, Elena P Morrissey, Ina Woods, Marion C Hogg, Sara Vianello, Morten T Venø, Jørgen Kjems, Gianni Sorarù, Caterina Bendotti, Jochen H M Prehn, Giovanni Nardo.

  Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease with no effective treatments, in part caused by variations in progression and the absence of biomarkers. Mice carrying the SOD1G93A transgene with different genetic backgrounds show variable disease rates, reflecting the diversity of patients. While extensive research has been done on the involvement of the central nervous system, the role of skeletal muscle remains underexplored. We examined the impact of angiogenin, including its RNase activity, in skeletal muscles of ALS mouse models and in biopsies from ALS patients. Elevated levels of angiogenin were found in slowly progressing mice but not in rapidly progressing mice, correlating with increased muscle regeneration and vascularisation. In patients, higher levels of angiogenin in skeletal muscles correlated with milder disease. Mechanistically, angiogenin promotes muscle regeneration and vascularisation through satellite cell-endothelial interactions during myogenesis and angiogenesis. Furthermore, specific angiogenin-derived tiRNAs were upregulated in slowly progressing mice, suggesting their role in mediating the effects of angiogenin. These findings highlight angiogenin and its tiRNAs as potential prognostic markers and therapeutic targets for ALS, offering avenues for patient stratification and interventions to mitigate disease progression by promoting muscle regeneration.

Keywords:  Angiogenin; amyotrophic lateral sclerosis; biomarkers; skeletal muscle; tiRNAs

DOI:  https://doi.org/10.1111/bpa.13328
FASEB J. 2024 Dec 13. 38(24): e70193

An immunohistochemical evaluation of fast twitch muscle formation induced by repeated administration of flavan 3-ols in mice.

Yamato Yoshida, Kenta Shimizu, Hitomi Nakamura, Yasuyuki Fujii, Tilman Fritsch, Ali Abdelhameed, Vittorio Calabrese, Naomi Osakabe.

  Flavan-3-ols (FL) are poorly bioavailable astringent polyphenols that induce hyperactivation of the sympathetic nervous system. The aim of this study was to investigate the effects of repeated oral administration of FL on mice hindlimb skeletal muscle using immunohistochemical techniques. C57BL/6J male mice were orally administered 50 mg/kg of FL for a period of 2 weeks, and bromideoxyuridine (BrdU) was administered intraperitoneally 3 days prior to the dissection. The soleus and extensor digitorum longus (EDL) were excised and prepared for frozen sections. Myosin heavy chain (MHC) antibodies were used to classify muscle types, in addition, muscle cross-sectional areas (CSA) were measured. We observed a shift in the peak of CSA in the soleus muscle and to a larger extent in the EDL. In addition, a distinct shift toward fast muscle was detected, documented by a reduction in type I and an increase in type IIb in the soleus muscle, whereas in the EDL, we observed a decline in type IIa and an expansion in type IIb. Incorporation of BrdU into cells was significantly increased in all skeletal muscles, with a significant increase in cells co-expressing pair box 7 (Pax7), a marker of differentiation, as observed in the EDL. Given the evidence that β2-adrenergic receptors in skeletal muscles regulate differentiation and size, we measured plasma catecholamine (CA) concentrations following a single differentiation of FL. A single oral dose of FL was observed to significantly increase plasma CA. These findings indicate that catecholamines secreted into the bloodstream from the adrenal gland following oral administration of FL may influence skeletal muscle size and type via β2-receptors.

Keywords:  Pax‐7; adrenergic receptor; extensor digitorum longus; flavan 3‐ols; myosin heavy chain; soleus

DOI:  https://doi.org/10.1096/fj.202401865R
Gene. 2024 Dec 24. pii: S0378-1119(24)01070-9. [Epub ahead of print] 149189

Circular RNAs and host genes act synergistically in regulating cellular processes and functions in skeletal myogenesis.

Chiu-Jung Huang, Kong Bung Choo.

  Circular RNAs (circRNAs) are post-transcriptional regulators generated from backsplicing of pre-mRNAs of host genes. A major circRNA regulatory mechanism involves microRNA (miRNA) sequestering, relieving miRNA-blocked mRNAs for translation and functions. To investigate possible circRNA-host gene relationship, skeletal myogenesis is chosen as a study model for its developmental importance and for readily available muscle tissues from farm animals for studies at different myogenic stages. This review aims to provide an integrated interpretations on methodologies, regulatory mechanisms and possible host gene-circRNA synergistic functional relationships in skeletal myogenesis, focusing on myoblast differentiation and proliferation, core drivers of muscle formation in myogenesis, while other myogenic processes that play supportive roles in the structure, maintenance and function of muscle tissues are also briefly discussed. On literature review,thirty-two circRNAs derived from thirty-one host genes involved in various myogenic stages are identified; twenty-two (68.6 %) of these circRNAs regulate myogenesis by sequestering miRNAs to engage PI3K/AKT and other signaling pathways while four (12.5 %) are translated into proteins for functions. In circRNA-host gene relationship,ten (32.3 %) host genes are shown to regulate myogenesis,nine (29.0 %) are specific to skeletal muscle functions,and twelve (38.8 %) are linked to skeletal muscle disorders.Our analysis of skeletal myogenesis suggests that circRNAs and host genes act synergistically to regulate cellular functions. Such circRNA-host gene functional synergism may also be found in other major cellular processes. CircRNAs may have evolved later than miRNAs to counteract the suppressive effects of miRNAs and to augment host gene functions to further fine-tune gene regulation.

Keywords:  CircRNA structure; MiRNA sponging; Muscular disorders; Myoblast differentiation; Satellite cells; Skeletal muscle; Skeletal myogenesis

DOI:  https://doi.org/10.1016/j.gene.2024.149189
Skelet Muscle. 2024 Dec 23. 14(1): 36

Comparative lipidomic and metabolomic profiling of mdx and severe mdx-apolipoprotein e-null mice.

Ram B Khattri, Abhinandan Batra, Zoe White, David Hammers, Terence E Ryan, Elisabeth R Barton, Pascal Bernatchez, Glenn A Walter.

  Despite its notoriously mild phenotype, the dystrophin-deficient mdx mouse is the most common model of Duchenne muscular dystrophy (DMD). By mimicking a human DMD-associated metabolic comorbidity, hyperlipidemia, in mdx mice by inactivating the apolipoprotein E gene (mdx-ApoE) we previously reported severe myofiber damage exacerbation via histology with large fibro-fatty infiltrates and phenotype humanization with ambulation dysfunction when fed a cholesterol- and triglyceride-rich Western diet (mdx-ApoEW). Herein, we performed comparative lipidomic and metabolomic analyses of muscle, liver and serum samples from mdx and mdx-ApoEW mice using solution and high-resolution-magic angle spinning (HR-MAS) 1H-NMR spectroscopy. Compared to mdx and regular chow-fed mdx-ApoE mice, we observed an order of magnitude increase in lipid deposition in gastrocnemius muscle of mdx-ApoEW mice including 11-fold elevations in -CH3 and -CH2 lipids, along with pronounced elevations in serum cholesterol, fatty acid, triglyceride and phospholipids. Hepatic lipids were also elevated but did not correlate with the extent of muscle lipid infiltration or differences in serum lipids. This study provides the first lipometabolomic signature of severe mdx lesions exacerbated by high circulating lipids and lends credence to claims that the liver, the main regulator of whole-body lipoprotein metabolism, may play only a minor role in this process.

Keywords:  Duchenne; Fibrofatty infiltration; HR-MAS; Liver; Metabolism; Muscle; NMR

DOI:  https://doi.org/10.1186/s13395-024-00368-w
J Appl Physiol (1985). 2024 Dec 26.

Repeated hyperbaric oxygen exposure accelerates fatigue and impairs SR-calcium release in mice.

Heath G Gasier, Jack Kovach, Kris Porter.

  Breathing hyperoxic gas is common in diving and accelerates fatigue after prolonged and repeated exposure. The mechanism(s) remain unknown but may be related to increased oxidants that interfere with skeletal muscle calcium trafficking or impair aerobic ATP production. To determine these possibilities, C57BL/6J mice were exposed to hyperbaric oxygen (HBO2) for 4-h on three consecutive days or remained in room air. Post-final exposure, fatigue was determined by grip strength and run to exhaustion tests. Other measurements included indices of oxidant stress and antioxidant defenses, mitochondrial bioenergetics, caffeine-induced sarcoplasmic reticulum-calcium release, and S-nitrosylation of ryanodine receptor 1 (RyR1). Despite grip strength being unaffected by repeated HBO2 exposure, mean running time was reduced by 50%. In skeletal muscle from HBO2 exposed mice, superoxide production was significantly increased, resulting in elevated lipid and DNA (nuclear and mitochondrial) oxidation. Accompanying increased oxidant stress was a reduction in glutathione content and increased Sod1 and Hmox1 gene expression; Ucp3 mRNA was reduced. Mitochondrial respiration, membrane potential, and NAD+/NADH were not influenced by HBO2. In contrast, caffeine induced SR-calcium release was reduced by 66% and S-nitrosylation of RyR1 was increased by 45%. Exposing mice to repeated HBO2 increases oxidant stress that activates some antioxidant responses. Mitochondrial function is not altered and could be related to decreased production of UCP3 that serves to maintain the electrochemical proton gradient. S-nitrosylation of RyR1 may promote SR-calcium leak and reduce content, a potential mechanism for repeated HBO2-induced fatigue.

Keywords:  Diving; S-nitrosylation; mitochondria; oxidants; ryanodine receptor type 1

DOI:  https://doi.org/10.1152/japplphysiol.00723.2024
Muscle Nerve. 2024 Dec 23.

Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.

Benjamin Chatel, Isabelle Varlet, Augustin C Ogier, Emilie Pecchi, Monique Bernard, Julien Gondin, Håkan Westerblad, David Bendahan, Charlotte Gineste.

   INTRODUCTION AND AIMS: Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production.
METHODS: Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy.
RESULTS: Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice.
DISCUSSION: The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca2+ accumulation.

Keywords:  force production; mitochondrial function; muscle disease; pharmacological agent; preclinical model

DOI:  https://doi.org/10.1002/mus.28315
Clin Sci (Lond). 2024 Dec 24. 138(24): 1561-1577

Muscle mass, muscle strength and the renin-angiotensin system.

Hikari Takeshita, Koichi Yamamoto, Masaki Mogi, Hiromi Rakugi.

  The renin-angiotensin system (RAS) is a classically known circulatory regulatory system. In addition to the previously known multi-organ circulatory form of the RAS, the existence of tissue RASs in individual organs has been well established. Skeletal muscle has also been identified as an organ with a distinct RAS. In recent years, the effects of RAS activation on skeletal muscle have been elucidated from several perspectives: differences in motor function due to genetic polymorphisms of RAS components, skeletal muscle dysfunction under conditions of excessive RAS activation such as heart failure, and the effects of the use of RAS inhibitors on muscle strength. In addition, the concept of the RAS itself has recently been expanded with the discovery of a 'protective arm' of the RAS formed by factors such as angiotensin-converting enzyme 2 and angiotensin 1-7. This has led to a new understanding of the physiological function of the RAS in skeletal muscle. This review summarizes the diverse physiological functions of the RAS in skeletal muscle and considers the potential of future therapeutic strategies targeting the RAS to overcome problems such as sarcopenia and muscle weakness associated with chronic disease.

Keywords:  angiotensins; motor function; renin-angiotensin system; skeletal muscle

DOI:  https://doi.org/10.1042/CS20220501
Heliyon. 2024 Dec 30. 10(24): e40772

Proteomics and machine learning: Leveraging domain knowledge for feature selection in a skeletal muscle tissue meta-analysis.

Alireza Shahin-Shamsabadi, John Cappuccitti.

  Omics techniques, such as proteomics, contain crucial data for understanding biological processes, but they remain underutilized due to their high dimensionality. Typically, proteomics research focuses narrowly on using a limited number of datasets, hindering cross-study comparisons, a problem that can potentially be addressed by machine learning. Despite this potential, machine learning has seen limited adoption in the field of proteomics. Here, skeletal muscle proteomics datasets from five separate studies were combined. These studies included conditions such as in vitro models (both 2D and 3D), in vivo skeletal muscle tissue, and adjacent tissues such as tendons. The collected data was preprocessed using MaxQuant, and then enriched using a Python script fetching structural and compositional details from UniProt and Ensembl databases. This was used to handle high-dimensional and sparsely labeled dataset by breaking it down into five smaller categories using cellular composition information and then training a Random Forest model for each category separately. Using biological context for interpreting the data resulted in improved model performance and made tailored analysis possible by reducing the dimensionality and increasing signal-to-noise ratio as well as only preserving biologically relevant features in each category. This integration of domain knowledge into data analysis and model training facilitated the discovery of new patterns while ensuring the retention of critical details, often overlooked when blind feature selection methods are used to exclude proteins with minimal expressions or variances. This approach was shown to be suitable for performing diverse analyses on individual as well as combined datasets within a broader biological context, ultimately leading to the identification of biologically relevant patterns. Besides from generating new biological insights, this approach can be used to perform tasks such as biomarker discovery, cluster analysis, classification, and anomaly detection more accurately, but incorporation of more datasets is needed to further expand the computational capabilities of such models in clinical settings.

Keywords:  Domain knowledge; Feature selection; Machine learning; Proteomics; Skeletal muscle tissue

DOI:  https://doi.org/10.1016/j.heliyon.2024.e40772