bims-moremu 2024-12-15 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–12–15
27 papers selected by
Anna Vainshtein, Craft Science Inc.

Myonuclear and satellite cell content of the vastus lateralis and soleus with70 days of simulated microgravity and the NASA SPRINT exercise program.
An IL-6 promoter variant (-174 G/C) augments IL-6 production and alters skeletal muscle transcription in response to exercise in mice.
Arginase-II gene deficiency reduces skeletal muscle aging in mice.
The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice.
Metabolic regulation in adult and aging skeletal muscle stem cells.
Exercise-Induced Methylation of the Serhl2 Promoter and Implication for Lipid Metabolism in Rat Skeletal Muscle.
Mll4 in Skeletal Muscle Fiber Maintains Muscle Stem Cells by Regulating Notch Ligands.
Peroxiredoxin 2 mediates redox-stimulated adaptations to oxidative phosphorylation induced by contractile activity in human skeletal muscle myotubes.
Recycle, Repair, Recover: The Role of Autophagy in Modulating Skeletal Muscle Repair and Post-Exercise Recovery.
Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.
Epigenetic control of myogenic identity of human muscle stem cells in Duchenne muscular dystrophy.
The skeletal muscle proteomic determinants of neuromuscular function in young and older women following 8 weeks of resistance training.
Single-nucleus transcriptomic analysis reveals the regulatory circuitry of myofiber XBP1 during regenerative myogenesis.
Delphinidin induces a fast-to-slow muscle fiber type shift through the AMPK signaling pathway in C2C12 myotubes.
Sulforaphane, Urolithin A, and ZLN005 induce time-dependent alterations in antioxidant capacity, mitophagy, and mitochondrial biogenesis in muscle cells.
Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling.
The CB1 antagonist Rimonabant improves muscle regeneration and remodels the inflammatory and endocannabinoid profile upon injury in male mice.
Circulating small extracellular vesicles as blood-based biomarkers of muscle health in aging nonhuman primates.
Hydroxyapatite nanoparticle mediated delivery of full length dystrophin gene as a potential therapeutic for the treatment of Duchenne muscular dystrophy.
Comparison of long and short rest periods during high-intensity interval exercise on transcriptomic responses in equine skeletal muscle.
Native DGC structure rationalizes muscular dystrophy-causing mutations.
Effects and mechanisms of APP and its cleavage product Aβ in the comorbidity of sarcopenia and Alzheimer's disease.
Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency.
Structure and assembly of the dystrophin glycoprotein complex.
The core circadian clock factor, Bmal1, transduces sex-specific differences in both rhythmic and non-rhythmic gene expression in the mouse heart.
Honoring Bengt Saltin: A Decade of Reflection on His Legacy in Exercise Physiology.
Reproductive aging research as a gateway to health and wellbeing.

J Appl Physiol (1985). 2024 Dec 10.

Myonuclear and satellite cell content of the vastus lateralis and soleus with70 days of simulated microgravity and the NASA SPRINT exercise program.

Chad M Skiles, Gerard Boyd, Aaron Gouw, Ethan Robbins, Kiril Minchev, Jeffrey Ryder, Lori Ploutz-Snyder, Todd A Trappe, Scott Trappe.

  We previously observed a range of whole muscle and individual slow and fast myofiber size responses (mean: +4 to -24%) in quadriceps (vastus lateralis) and triceps surae (soleus) muscles of individuals undergoing 70 days of simulated microgravity with or without the NASA SPRINT exercise countermeasures program. The purpose of the current investigation was to further explore, in these same individuals, the content of myonuclei and satellite cells, both of which are key regulators of skeletal muscle mass. Individuals completed 6° head-down-tilt bedrest (BR, n=9), bedrest with resistance and aerobic exercise (BRE, n=9), or bedrest with resistance and aerobic exercise and low-dose testosterone (BRE+T, n=8). The number of myonuclei and satellite cells associated with each slow (myosin heavy chain (MHC) I) and fast (MHC IIa) myofiber in the vastus lateralis was not changed (P>0.05) pre- to post-bedrest within the BR, BRE, or BRE+T groups. Similarly, in the soleus the number of myonuclei associated with each slow and fast myofiber, and the number of satellite cells associated with each slow myofiber were not changed (P>0.05) pre- to post-bedrest within the BR, BRE, or BRE+T groups. It appears that even with relatively large perturbations in muscle mass over a few months of simulated microgravity, or with partially or completely effective exercise countermeasures, human skeletal muscle tightly regulates the abundance of myonuclei and satellite cells. Thus, exercise countermeasures efficacy for skeletal muscle atrophy appears to be independent of myonuclei and satellite cell abundance.

Keywords:  bedrest; exercise; microgravity; myonuclei; satellite cell; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00468.2024
J Appl Physiol (1985). 2024 Dec 12.

An IL-6 promoter variant (-174 G/C) augments IL-6 production and alters skeletal muscle transcription in response to exercise in mice.

L E Watson, C L MacRae, P Kallingappa, Y Cao, X Li, C P Hedges, R F D'Souza, N Fleming, K M Mellor, T L Merry.

  Interleukin-6 (IL-6) is produced and secreted by skeletal muscle cells during exercise and plays an important role in mediating metabolic responses to exercise. The promoter region of the IL-6 gene contains a common genetic variant (-174 G/C, rs1800795) which may alter responses to exercise training. To isolate the impact of this gene variant on exercise-induced IL-6 expression and skeletal muscle transcription responses following exercise we generated knock-in mice with a GG or variant CC genotype for the murine homolog of rs1800795. The overall gross metabolic phenotype of resting mice was similar between genotypes; however, following acute treadmill running the variant CC genotype was associated with a greater increase in skeletal muscle IL-6 mRNA and circulating IL-6. Furthermore, we observed that mice with the variant CC genotype exhibited sex-specific differences in skeletal muscle master metabolism regulatory genes, and had greater increases in genes controlling mitochondrial biogenesis in skeletal muscle post-exercise. However, there was no effect of genotype on exercise-induced skeletal muscle glycogen depletion, circulating free fatty acids, blood glucose and lactate production, or exercise-responsive gene expression in subcutaneous fat. These findings suggest that the IL-6 promoter variant -174 G/C may result in enhanced skeletal muscle adaptations in response to exercise training, and could mean that individuals with the 'C' allele may more readily gain improvements in metabolic health in response to exercise training.

Keywords:  exercise; genetic variant; interleukin-6; metabolism; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00391.2024
Aging (Albany NY). 2024 Dec 12. null

Arginase-II gene deficiency reduces skeletal muscle aging in mice.

Matteo Caretti, Duilio Michele Potenza, Guillaume Ajalbert, Urs Albrecht, Xiu-Fen Ming, Andrea Brenna, Zhihong Yang.

  Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (wt) mice and mice deficient in arg-ii (arg-ii-/-) of both sexes are investigated. We demonstrate a decreased physical performance of old wt mice, which is partially prevented in arg-ii-/- animals, particularly in males. The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice. Finally, we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.

Keywords:  aging; arginase-II; cellular senescence; fibrosis; physical activity; skeletal muscle

DOI:  https://doi.org/10.18632/aging.206173
bioRxiv. 2024 Nov 25. pii: 2024.11.25.625261. [Epub ahead of print]

The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice.

Soomin Cho, Emilia Servián-Morilla, Victoria Navarro Garrido, Beatriz Rodriguez-Gonzalez, Youxi Yuan, Raquel Cano, Arjun A Rambhiya, Radbod Darabi, Robert S Haltiwanger, Carmen Paradas, Hamed Jafar-Nejad.

Mutations in protein O -glucosyltransferase 1 ( POGLUT1 ) cause a recessive form of limb-girdle muscular dystrophy (LGMD-R21) associated with reduced satellite cell number and NOTCH1 signaling in adult patient muscles and impaired myogenic capacity of patient-derived muscle progenitors. However, the in vivo roles of POGLUT1 in the development, function, and maintenance of satellite cells are not well understood. Here, we show that conditional deletion of mouse Poglut1 in myogenic progenitors leads to early lethality, postnatal muscle growth defects, reduced Pax7 expression, abnormality in muscle extracellular matrix, and impaired muscle repair. Poglut1 -deficient muscle progenitors exhibit reduced proliferation, enhanced differentiation, and accelerated fusion into myofibers. Inducible loss of Poglut1 in adult satellite cells leads to their precocious differentiation and impairs muscle repair upon serial injury. Cell-based signaling assays and mass spectrometric analysis indicate that POGLUT1 is required for the activation of NOTCH1, NOTCH2, and NOTCH3 in myoblasts and that NOTCH3 is a target of POGLUT1 like NOTCH1 and NOTCH2. These observations provide insight into the roles of POGLUT1 in muscle development and repair and the pathophysiology of LGMD-R21.

DOI: https://doi.org/10.1101/2024.11.25.625261
Genes Dev. 2024 Dec 11.

Metabolic regulation in adult and aging skeletal muscle stem cells.

Vittorio Sartorelli, Veronica Ciuffoli.

  Adult stem cells maintain homeostasis and enable regeneration of most tissues. Quiescence, proliferation, and differentiation of stem cells and their progenitors are tightly regulated processes governed by dynamic transcriptional, epigenetic, and metabolic programs. Previously thought to merely reflect a cell's energy state, metabolism is now recognized for its critical regulatory functions, controlling not only energy and biomass production but also the cell's transcriptome and epigenome. In this review, we explore how metabolic pathways, metabolites, and transcriptional and epigenetic regulators are functionally interlinked in adult and aging skeletal muscle stem cells.

Keywords:  adult stem cells; epigenetics; metabolism; muscle regeneration; muscle stem cells; transcription

DOI:  https://doi.org/10.1101/gad.352277.124
Mol Metab. 2024 Dec 08. pii: S2212-8778(24)00212-6. [Epub ahead of print] 102081

Exercise-Induced Methylation of the Serhl2 Promoter and Implication for Lipid Metabolism in Rat Skeletal Muscle.

Mutsumi Katayama, Kazuhiro Nomura, Jonathan M Mudry, Alexander V Chibalin, Anna Krook, Juleen R Zierath.

   OBJECTIVE: Environmental factors such as physical activity induce epigenetic modification, with exercise-responsive DNA methylation changes occurring in skeletal muscle. To determine the skeletal muscle DNA methylation signature to endurance swim training we used whole-genome methylated DNA immunoprecipitation (MeDIP) sequencing.
RESULTS: Gene set expression analysis (GSEA) of differentially methylated promoter regions (DMRs) an enrichment of four gene sets, including those annotated to lipid metabolic process, with differentially hypermethylated or hypomethylated promoter regions in skeletal muscle of exercise-trained rats. Single base resolution bisulfite sequencing confirmed that neighboring CpGs in the transcription start site of Serhl2 (Serine Hydrolase Like 2) were hypomethylated in exercise-trained rats. Serhl2 gene expression was upregulated in exercise-trained rats, as well as in an exercise-in-a-dish model of L6 myotubes subjected to electrical pulse stimulation (EPS). Serhl2 promoter activity was regulated by methylation, and in response to EPS. We identified a Nr4a binding motif in the Serhl2 promoter region, which upon deletion, reduced Serhl2 promoter activity and abolished sensitivity to methylation in L6 myotubes. Gene silencing of Serhl2 in L6 myotubes reduced both intracellular lipid oxidation and triacylglycerol synthesis in response to EPS.
CONCLUSION: Exercise training promotes intracellular lipid metabolism and phenotypic changes in skeletal muscle through epigenomic modifications on Serine Hydrolase Like 2. Hypomethylation of Serhl2 promoter affects transcription factor binding of Nr4a, Serhl2 promoter activity, and Serhl2 mRNA expression in skeletal muscle. Our data link exercise-induced epigenomic regulation Serhl2 with lipid oxidation and triacylglycerol synthesis in skeletal muscle.

Keywords:  DNA methylation; Exercise training; Lipid metabolism; Promoter activity; Serine hydrolase like 2; Skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.102081
Res Sq. 2024 Nov 26. pii: rs.3.rs-5413133. [Epub ahead of print]

Mll4 in Skeletal Muscle Fiber Maintains Muscle Stem Cells by Regulating Notch Ligands.

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. Therefore, it is crucial to investigate the regulatory mechanisms governing the transition of MuSC states across different postnatal developmental stages. Methods To assess if myofiber-expressed Mll4 contributes to the maintenance of MuSCs, we crossed MCK Cre/+ or HSA MerCreMer/+ mice to Mll4 f/f mice to generate myofiber-specific Mll4 -deleted mice. Investigations were conducted using 8-week-old and 4-week-old MCK Cre/+ ; Mll4 f/f mice Investigations were conducted using 8-week-old and 4-week-old HSA Cre/+ ; Mll4 f/f mice were utilized. 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.

DOI: https://doi.org/10.21203/rs.3.rs-5413133/v1
Free Radic Biol Med. 2024 Dec 04. pii: S0891-5849(24)01097-9. [Epub ahead of print]227 395-406

Peroxiredoxin 2 mediates redox-stimulated adaptations to oxidative phosphorylation induced by contractile activity in human skeletal muscle myotubes.

Robert A Heaton, Sam Tm Ball, Caroline A Staunton, Vincent Mouly, Samantha W Jones, Anne McArdle, Malcolm J Jackson.

Skeletal muscle generates superoxide during contractions, which is converted to hydrogen peroxide (H2O2). H2O2 has been proposed to activate signalling pathways and transcription factors that regulate adaptive responses to exercise, but the concentration required to oxidize and activate key redox-sensitive signalling proteins in vitro is much higher than the typical intracellular levels seen in muscle after exercise. We hypothesized that 2-Cys-peroxiredoxins (PRDX), which rapidly oxidize in the presence of physiological concentrations of H2O2, serve as intermediary signalling molecules and play a crucial role in activating adaptive pathways following muscle contractions. This study has examined the human muscle myotube responses to contractile activity, or exposure to low extracellular concentrations (2.5-5 μM) of H2O2 and whether knock down of muscle PRDX2 alters the differential gene expression (DEG) that results from these stresses. Exposure of human skeletal muscle myotubes to a 15 min period of aerobic electrically stimulated isometric contractions or 5 μM H2O2 induced substantial changes in DEG with modification of many genes associated with adaptations of skeletal muscle to contractile activity. Common DEG in these conditions included upregulation of genes associated with increased mitochondrial oxidative phosphorylation, including COX1, COX2, COX3 and ATP6. In myotubes with PRDX2 knock down (94 % decrease in PRDX2 mRNA), the upregulation of genes associated with increased mitochondrial oxidative phosphorylation was abolished following contractile activity or exposure to H2O2. These data indicate that a common effect of contractile activity and exposure to "physiological" levels of H2O2 in human myotubes is to increase the expression of multiple genes associated with increased mitochondrial oxidative phosphorylation. Furthermore, these effects were abolished in PRDX2 knock down myotubes indicating that adaptations to upregulate multiple genes related to increased mitochondrial capacity in human muscle myotubes in response to exercise is both redox regulated and requires PRDX2 as an essential mediator of the effects of H2O2.

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.11.053
Biosci Rep. 2024 Dec 13. pii: BSR20240137. [Epub ahead of print]

Recycle, Repair, Recover: The Role of Autophagy in Modulating Skeletal Muscle Repair and Post-Exercise Recovery.

Jordan Acheson, Sophie Joanisse, Craig Sale, Nathan Hodson.

  Skeletal muscle is a highly plastic tissue which can adapt relatively rapidly to a range of stimuli. In response to novel mechanical loading, e.g. unaccustomed resistance exercise, myofibers are disrupted and undergo a period of ultrastructural remodelling to regain full physiological function, normally within 7 days. The mechanisms which underpin this remodelling are believed to be a combination of cellular processes including UPS/Calpain-mediated degradation, immune cell infiltration and satellite cell proliferation/differentiation. A relatively understudied cellular system which has the potential to be a significant contributing mechanism to repair and recovery is autophagolysosomal system, a cellular process which degrades damaged and dysfunctional cellular components to provide constituent components for the resynthesis of new organelles and cellular structures. This review summarises our current understanding of the autophagolysosomal system in the context of skeletal muscle repair and recovery. In addition, we also provide hypothetical models of how this system may interact with other processes involved in skeletal muscle remodelling and provide avenues for future research to improve our understanding of autophagy in human skeletal muscle.

Keywords:  autophagy; damage; exercise; recovery; skeletal muscle

DOI:  https://doi.org/10.1042/BSR20240137
Am J Physiol Cell Physiol. 2024 Dec 13.

Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.

Sabrina Champsi, David A Hood.

  Mitochondria are metabolic hubs that govern skeletal muscle health. While exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined Sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial ROS emission. Signaling towards biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggests that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.

Keywords:  Nrf-2; PGC-1α; exercise; mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00669.2024
iScience. 2024 Dec 20. 27(12): 111350

Epigenetic control of myogenic identity of human muscle stem cells in Duchenne muscular dystrophy.

Jimmy Massenet, Michèle Weiss-Gayet, Hina Bandukwala, Wilhelm Bouchereau, Stéphanie Gobert, Mélanie Magnan, Arnaud Hubas, Patrick Nusbaum, Isabelle Desguerre, Cyril Gitiaux, F Jeffrey Dilworth, Bénédicte Chazaud.

  In Duchenne muscular dystrophy (DMD), muscle stem cells' (MuSCs) regenerative capacities are overwhelmed leading to fibrosis. Whether MuSCs have intrinsic defects or are disrupted by their environment is unclear. We investigated cell behavior and gene expression of MuSCs from DMD or healthy human muscles. Proliferation, differentiation, and fusion were unaltered in DMD-MuSCs, but with time, they lost their myogenic identity twice as fast as healthy MuSCs. The rapid drift toward a fibroblast-like cell identity was observed at the clonal level, and resulted from altered expression of epigenetic enzymes. Re-expression of CBX3, SMC3, H2AFV, and H3F3B prevented the MuSC identity drift. Among epigenetic changes, a closing of chromatin at the transcription factor MEF2B locus caused downregulation of its expression and loss of the myogenic fate. Re-expression of MEF2B in DMD-MuSCs restored their myogenic fate. MEF2B is key in the maintenance of myogenic identity in human MuSCs, which is altered in DMD.

Keywords:  Epigenetics; Integrative aspects of cell biology; Stem cells research

DOI:  https://doi.org/10.1016/j.isci.2024.111350
Exp Physiol. 2024 Dec 11.

The skeletal muscle proteomic determinants of neuromuscular function in young and older women following 8 weeks of resistance training.

Mary O'Leary, Elsa Greed, Jack Pritchard, Lauren Struszczak, Esra Bozbaş, Joanna Bowtell.

  Resistance training (RT) is the gold standard intervention for ameliorating sarcopenia. Outstanding mechanistic questions remain regarding the malleability of the molecular determinants of skeletal muscle function in older age. Discovery of proteomics can expand such knowledge. We aimed to compare the effect of RT on the skeletal muscle proteome and neuromuscular function (NMF) in older and younger women. Seven young (22 ± 6 years) and eight older (63 ± 5 years) women completed 8 weeks' leg RT. Pre- and post-training, measures of leg and handgrip strength, NMF and vastus lateralis (VL) biopsies were obtained. Tandem-mass-tagged skeletal muscle proteomic analyses were performed. Data were analysed using differential expression and weighted gene co-expression network approaches. Proteins related to skeletal muscle contraction were lower in older skeletal muscle; this was not normalised by RT. Following RT, older women had higher expression of VL mitochondrial biogenesis proteins compared to the young, a reversal of pre-training observations. Seventy proteins were differentially expressed between age groups. VL expression of these proteins in older women was consistently and significantly associated with poorer leg strength/NMF. Conversely, VL expression of these proteins in older women was often associated with greater handgrip strength. This study has identified important differences in the molecular responses of young and old skeletal muscle to RT. We have demonstrated their close relationship with skeletal muscle function. Proteins that are refractory to RT may represent targets to ameliorate sarcopenia. We have described a 'proteomic-function' relationship that appears to be muscle-specific. Future research should further unpick these complex relationships.

Keywords:  exercise; proteomics; resistance training; skeletal muscle; strength

DOI:  https://doi.org/10.1113/EP092328
iScience. 2024 Dec 20. 27(12): 111372

Single-nucleus transcriptomic analysis reveals the regulatory circuitry of myofiber XBP1 during regenerative myogenesis.

Aniket S Joshi, Micah B Castillo, Meiricris Tomaz da Silva, Anh Tuan Vuong, Preethi H Gunaratne, Radbod Darabi, Yu Liu, Ashok Kumar.

  Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is activated in skeletal muscle under multiple conditions. However, the role of the UPR in the regulation of muscle regeneration remains less understood. We demonstrate that gene expression of various markers of the UPR is induced in both myogenic and non-myogenic cells in regenerating muscle. Genetic ablation of X-box binding protein 1 (XBP1), a downstream target of the Inositol requiring enzyme 1α (IRE1α) arm of the UPR, in myofibers attenuates muscle regeneration in adult mice. Single nucleus RNA sequencing (snRNA-seq) analysis showed that deletion of XBP1 in myofibers perturbs proteolytic systems and mitochondrial function in myogenic cells. Trajectory analysis of snRNA-seq dataset showed that XBP1 regulates the abundance of satellite cells and the formation of new myofibers in regenerating muscle. In addition, ablation of XBP1 disrupts the composition of non-myogenic cells in injured muscle microenvironment. Collectively, our study suggests that myofiber XBP1 regulates muscle regeneration through both cell-autonomous and -non-autonomous mechanisms.

Keywords:  Biochemistry; Cell biology; Genetics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.111372
Biochem Biophys Rep. 2024 Dec;40 101884

Delphinidin induces a fast-to-slow muscle fiber type shift through the AMPK signaling pathway in C2C12 myotubes.

Motoki Murata, Rina Takahashi, Yuki Marugame, Yoshinori Fujimura, Hirofumi Tachibana.

  Delphinidin, a plant anthocyanidin, suppresses disuse muscle atrophy in mice. However, its effect on muscle fiber type shift is unclear. To examine whether delphinidin affects skeletal muscle fiber type, differentiated C2C12 cells were treated with delphinidin. Results revealed that delphinidin upregulated the mRNA expression of myosin heavy chain type I (MyHCI), troponin C1, troponin I1, and MyHCIIx and increased slow MyHC protein level in C2C12 myotubes. Delphinidin also enhanced succinic dehydrogenase (SDH) activities and suppressed lactate dehydrogenase (LDH) activity. Adenosine monophosphate-activated protein kinase (AMPK) inhibition attenuated delphinidin-induced MyHCI upregulation and MyHCIIb downregulation. We investigated the effect of delphinidin on the upstream factors involved in AMPK activation. Delphinidin increased liver kinase B1 (LKB1) phosphorylation and nuclear respiratory factor 1 (NRF1) and calcium/calmodulin-dependent protein kinase 2 (CaMKK2) protein levels. In conclusion, delphinidin induced muscle fiber type conversion from fast-twitch to slow-twitch muscles through the AMPK signaling pathway.

Keywords:  AMPK; Anthocyanidin; C2C12 myotube; MyHC

DOI:  https://doi.org/10.1016/j.bbrep.2024.101884
Sports Med Health Sci. 2025 Jan;7(1): 16-27

Sulforaphane, Urolithin A, and ZLN005 induce time-dependent alterations in antioxidant capacity, mitophagy, and mitochondrial biogenesis in muscle cells.

Neushaw Moradi, Sabrina Champsi, David A Hood.

  Efficient signal transduction that mediates mitochondrial turnover is a strong determinant of metabolic health in skeletal muscle. Of these pathways, our focus was aimed towards the enhancement of antioxidant capacity, mitophagy, and mitochondrial biogenesis. While physical activity is an excellent inducer of mitochondrial turnover, its ability to ubiquitously activate and enhance mitochondrial turnover prevents definitive differentiation of the contribution made by each pathway. Therefore, we employed three agents, Sulforaphane (SFN), Urolithin A (UroA), and ZLN005 (ZLN), which are activators of important biological markers involved in antioxidant signaling, mitophagy, and biogenesis, respectively. We investigated the time-dependent changes in proteins related to each mechanism in C2C12 myotubes. SFN treatment resulted in increased nuclear localization of the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) after 4 hour (h), with subsequent 2-fold increases in the antioxidant enzymes Nicotinamide Quinone Oxidoreductase 1 (NQO1) and Heme-Oxygenase-1 (HO-1) by 24 h and 48 h. Mitochondrial respiration and ATP production were significantly increased by both 24 h and 48 h. UroA showed a 2-fold increase in AMP-activated Protein Kinase (AMPK) after 4 h, which led to a modest 30% increase in whole cell mitophagy markers p62 and LC3, after 48 h. This was accompanied by a reduction in cellular Reactive Oxygen Species (ROS), detected with the CellROX Green reagent. Mitophagy flux measurements showed mitophagy activation as both LC3-II and p62 flux increased with UroA at 24-h and 48-h time points, respectively. Finally, AMPK activation was observed by 4 h, in addition to a 2-fold increase in Mitochondrial Transcription Factor A (TFAM) promoter activity by 24 h of ZLN treatment following transient transfection of a TFAM promoter-luciferase construct. Mitochondrial respiration and ATP production were enhanced by 24 h. Our results suggest that early time points of treatment increase upstream pathway activity, whereas later time points represent the increased phenotypic expression of related downstream markers. Our findings suggest that the spatiotemporal progression of these mechanisms following drug treatment is another important factor to consider when examining subcellular changes towards mitochondrial turnover in muscle.

Keywords:  AMPK; Exercise mimetic; Mitochondria; Nrf-2; Skeletal muscle

DOI:  https://doi.org/10.1016/j.smhs.2024.03.011
NAR Mol Med. 2024 Oct;1(4): ugae016

Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling.

Jonathan C Mcleod, Changhyun Lim, Tanner Stokes, Jalil-Ahmad Sharif, Vagif Zeynalli, Lucas Wiens, Alysha C D'Souza, Lauren Colenso-Semple, James McKendry, Robert W Morton, Cameron J Mitchell, Sara Y Oikawa, Claes Wahlestedt, J Paul Chapple, Chris McGlory, James A Timmons, Stuart M Phillips.

A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customized RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n = 144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growth in vivo, while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, including CYTOR-which was leukocyte-associated (false discovery rate [FDR] = 4.9 × 10-7). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 × 10-8), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 × 10-5). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in vivo. Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways.

DOI: https://doi.org/10.1093/narmme/ugae016
Life Sci. 2024 Dec 05. pii: S0024-3205(24)00886-5. [Epub ahead of print] 123296

The CB1 antagonist Rimonabant improves muscle regeneration and remodels the inflammatory and endocannabinoid profile upon injury in male mice.

Sebastiaan Dalle, Moniek Schouten, Kaat Vanderbeke, Evy Van Parys, Monique Ramaekers, Martine Thomis, Domiziana Costamagna, Katrien Koppo.

  Skeletal muscle regeneration upon injury requires timely activation of inflammatory, myogenic, fibrotic, apoptotic and anabolic systems. Optimization of these features might improve the recovery process. Whereas recent data indicate that the endocannabinoid system, and more particularly cannabinoid receptor 1 (CB1) antagonism, is involved in the regulation of inflammatory, myogenic, fibrotic, apoptotic and anabolic pathways, it was never studied whether CB1 antagonism can improve muscle regeneration. The present study investigated the effect of the CB1 antagonist Rimonabant (10 mg/kg/d) on functional (5 days post-cardiotoxin injury; 5DPI) and molecular muscle responses (3DPI and 7DPI) in mice. Rimonabant prevented cardiotoxin-induced muscle strength loss 5DPI, increased myofiber growth (7DPI) and improved the muscle molecular profile 3DPI and 7DPI. In general, inflammation (e.g. p-p65NF-κB, CD80) and apoptosis (e.g. cleaved caspase-3, cleaved PARP) were downregulated by Rimonabant, whereas it upregulated the expression of Pax7 but other myogenic factors remained unaffected by rimonabant. In addition, Rimonabant restored the injury-induced (inflammatory) lipid profile to a large extent, including oxygenated fatty acids, unsaturated fatty acids and endocannabinoids such as 2-arachidonoyl glycerol and palmitoylethanolamide. Altogether, these data show that the endocannabinoid system might be a novel therapeutic target to improve muscle regeneration, which is relevant for age- and disease-related muscle degeneration.

Keywords:  Cannabinoid receptor 1; Cardiotoxin; Endocannabinoid system; Muscle regeneration; Muscle strength

DOI:  https://doi.org/10.1016/j.lfs.2024.123296
Geroscience. 2024 Dec 10.

Circulating small extracellular vesicles as blood-based biomarkers of muscle health in aging nonhuman primates.

Shalini Mishra, Ashish Kumar, Yangen He, Yixin Su, Sangeeta Singh, Mark F Santos, Rakesh Singh, Jingyun Lee, Cristina M Furdui, Carol A Shively, Stephen B Kritchevsky, Thomas C Register, Gagan Deep.

  Age-associated loss of muscle mass and function and subsequent mobility decline define poor health outcomes, reduced quality of life, and mortality risk. The rate and extent of aging-related muscle loss varies across older adults. It is challenging to understand the molecular pathogenesis of mobility decline, as anthropometric and imaging techniques, primarily used in muscle function assessment, do not offer much molecular information. Small extracellular vesicles (sEV) are lipid membrane-bound, nano-sized (≤ 200 nm) vesicles which carry a wide array of biomolecules as their cargo. sEV contain cell/tissue-specific signatures on their surface and can be isolated from biofluids. These properties pose sEV as a minimally invasive means to monitor the functional and biological health of difficult-to-access tissues, establishing them as a promising liquid biopsy tool. Here, we first isolated skeletal muscle-derived sEV (sEVSKM) from the serum of vervet monkeys (16 to < 25 years old) using alpha sarcoglycan (SGCA) as a muscle-specific sEV surface marker. sEVSKM were extensively characterized for size, concentration, purity, and specificity. Further, sEVSKM isolated from young (11-15 years) and old (25-29 years) monkeys' serum were characterized for oxidized proteins by mass spectrometry and miRNAs by small-RNAseq. Notably, the analysis of oxidized proteins indicated perturbation of metabolic pathways, actin cytoskeleton, muscle cytoskeleton regulation, and HIF-1 signaling in older monkeys. Furthermore, small-RNAseq analysis identified differential expression of several miRNAs regulating metabolic pathways, inflammation, and stress signaling. Altogether, these results suggest that it is feasible to isolate sEVSKM and use them to identify molecular biomarkers that reflect the physiological state of muscle tissue.

Keywords:  Aging; MicroRNA; Oxidized protein; Skeletal muscle; Skeletal muscle-derived small extracellular vesicle

DOI:  https://doi.org/10.1007/s11357-024-01439-y
Nanoscale. 2024 Dec 09.

Hydroxyapatite nanoparticle mediated delivery of full length dystrophin gene as a potential therapeutic for the treatment of Duchenne muscular dystrophy.

Pooja Kotharkar, Indrani Talukdar, Sutapa Roy Ramanan, Keerthi Ramesh, Arun Shastry, Meenal Kowshik.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, primarily affecting young males. In this study, we investigated arginine-modified hydroxyapatite nanoparticles (R-HAp) as a novel non-viral vector for DMD gene therapy, particularly for delivering the large 18.8 kb dystrophin gene. Addressing the limitations of traditional adeno-associated viral vectors, R-HAp demonstrated efficient binding and delivery of the dystrophin plasmid to DMD patient-derived skeletal muscle cells. Using confocal imaging and RT-PCR analysis, our results showed effective gene delivery and expression in both mouse myotubes and patient-derived cells, with sustained expression evident up to 5 days post transfection. The patient-derived myotubes also showed dystrophin protein production 7 days post transfection. These findings suggest R-HAp nanoparticles as a promising and cost-effective alternative for DMD treatment, highlighting their potential for overcoming current gene therapy challenges.

DOI: https://doi.org/10.1039/d4nr03906h
Physiol Genomics. 2024 Dec 11.

Comparison of long and short rest periods during high-intensity interval exercise on transcriptomic responses in equine skeletal muscle.

Kenya Takahashi, Kazutaka Mukai, Yuji Takahashi, Yusaku Ebisuda, Hideo Hatta, Yu Kitaoka.

  The purpose of this study was to elucidate the skeletal muscle transcriptomic response unique to rest duration during high-intensity interval exercise. Thoroughbred horses performed three 1-min bouts of exercise at their maximal oxygen uptake (10.7-12.5 m/s), separated by 15 min (long) or 2 min (short) walking at 1.7 m/s. Gluteus medius muscle was collected before and at 4 h after the exercise and used for RNA sequencing. We identified 1,756 and 1,421 differentially expressed genes in response to the long and short protocols, respectively using DEseq2 analysis [false discovery rate (FDR) cutoff = 0.05, minimal fold change = 1.5]. The overall transcriptional response was partially aligned, with 43% (n=949) of genes altered in both protocols, whereas no discordant directional changes were observed. K-means clustering and gene set enrichment analyses based on gene ontology biological process terms showed that genes associated with muscle adaptation and development were upregulated regardless of exercise conditions; genes related to immune and cytokine responses were more upregulated following the long protocol, and protein folding and temperature response were highly expressed after the short protocol. We found that 11 genes were upregulated to a greater extent by the short protocol and one was by the long protocol, with GNA13, SPART, PHAF1, and PTX3 identified as potential candidates for skeletal muscle remodeling. Our results suggest that altered metabolic fluctuations dependent on the intermittent pattern of interval exercise modulate skeletal muscle gene expression, and therefore rest interval length could be an important consideration in optimizing skeletal muscle adaptation.

Keywords:  High-intensity interval exercise; Skeletal muscle; Thoroughbred; Transcriptomics

DOI:  https://doi.org/10.1152/physiolgenomics.00066.2024
Nature. 2024 Dec 11.

Native DGC structure rationalizes muscular dystrophy-causing mutations.

Shiheng Liu, Tiantian Su, Xian Xia, Z Hong Zhou.

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality1,2. Discovery of the DMD gene encoding dystrophin both revealed the cause of DMD and helped identify a family of at least ten dystrophin-associated proteins at the muscle cell membrane, collectively forming the dystrophin-glycoprotein complex (DGC)3-9. The DGC links the extracellular matrix to the cytoskeleton, but, despite its importance, its molecular architecture has remained elusive. Here we determined the native cryo-electron microscopy structure of rabbit DGC and conducted biochemical analyses to reveal its intricate molecular configuration. An unexpected β-helix comprising β-, γ- and δ-sarcoglycan forms an extracellular platform that interacts with α-dystroglycan, β-dystroglycan and α-sarcoglycan, allowing α-dystroglycan to contact the extracellular matrix. In the membrane, sarcospan anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, while in the cytoplasm, β-dystroglycan's juxtamembrane fragment binds dystrophin's ZZ domain. Through these interactions, the DGC links laminin 2 to intracellular actin. Additionally, dystrophin's WW domain, along with its EF-hand 1 domain, interacts with α-dystrobrevin. A disease-causing mutation mapping to the WW domain weakens this interaction, as confirmed by deletion of the WW domain in biochemical assays. Our findings rationalize more than 110 mutations affecting single residues associated with various muscular dystrophy subtypes and contribute to ongoing therapeutic developments, including protein restoration, upregulation of compensatory genes and gene replacement.

DOI: https://doi.org/10.1038/s41586-024-08324-w
Front Aging Neurosci. 2024 ;16 1482947

Effects and mechanisms of APP and its cleavage product Aβ in the comorbidity of sarcopenia and Alzheimer's disease.

Jiale Wu, Jun Tang, Di Huang, Yu Wang, Enyuan Zhou, Qin Ru, Guodong Xu, Lin Chen, Yuxiang Wu.

  Sarcopenia and AD are both classic degenerative diseases, and there is growing epidemiological evidence of their comorbidity with aging; however, the mechanisms underlying the biology of their commonality have not yet been thoroughly investigated. APP is a membrane protein that is expressed in tissues and is expressed not only in the nervous system but also in the NMJ and muscle. Deposition of its proteolytic cleavage product, Aβ, has been described as a central component of AD pathogenesis. Recent studies have shown that excessive accumulation and aberrant expression of APP in muscle lead to pathological muscle lesions, but the pathogenic mechanism by which APP and its proteolytic cleavage products act in skeletal muscle is less well understood. By summarizing and analyzing the literature concerning the role, pathogenicity and pathological mechanisms of APP and its cleavage products in the nervous system and muscles, we aimed to explore the intrinsic pathological mechanisms of myocerebral comorbidities and to provide new perspectives and theoretical foundations for the prevention and treatment of AD and sarcopenia comorbidities.

Keywords:  AD; amyloid precursor protein; cleavage products; intervention; myocerebral comorbidity; sarcopenia

DOI:  https://doi.org/10.3389/fnagi.2024.1482947
J Gen Physiol. 2025 Jan 06. pii: e202413583. [Epub ahead of print]157(1):

Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency.

Amy D Hanna, Ting Chang, Kevin S Ho, Rachel Sue Zhen Yee, William Cameron Walker, Nadia Agha, Chih-Wei Hsu, Sung Yun Jung, Mary E Dickinson, Md Abul Hassan Samee, Christopher S Ward, Chang Seok Lee, George G Rodney, Susan L Hamilton.

Dilated cardiomyopathy (DCM) is a highly prevalent and genetically heterogeneous condition that results in decreased contractility and impaired cardiac function. The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the α-myosin heavy chain, (αMHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in adult hearts compared with control animals. However, only the early embryonic deletion of FKBP12 (αMHC-Cre) resulted in an early-onset and progressive DCM, increased cardiac oxidative stress, altered expression of proteins associated with cardiac remodeling and disease, and sarcoplasmic reticulum Ca2+ leak. Our findings indicate that FKBP12 deficiency during early development results in cardiac remodeling and altered expression of DCM-associated proteins that lead to progressive DCM in adult hearts, thus suggesting a major role for FKBP12 in embryonic cardiac muscle.

DOI: https://doi.org/10.1085/jgp.202413583
Nature. 2024 Dec 11.

Structure and assembly of the dystrophin glycoprotein complex.

Li Wan, Xiaofei Ge, Qikui Xu, Gaoxingyu Huang, Tiandi Yang, Kevin P Campbell, Zhen Yan, Jianping Wu.

The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix1-3. Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration4,5. Despite the important roles of the DGC in physiology and pathology, its structural details remain largely unknown, hindering a comprehensive understanding of its assembly and function. Here we isolated the native DGC from mouse skeletal muscle and obtained its high-resolution structure. Our findings unveil a markedly divergent structure from the previous model of DGC assembly. Specifically, on the extracellular side, β-, γ- and δ-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for α-sarcoglycan and dystroglycan. In the transmembrane region, sarcoglycans and sarcospan flank and stabilize the single transmembrane helix of dystroglycan, rather than forming a subcomplex as previously proposed6-8. On the intracellular side, sarcoglycans and dystroglycan engage in assembly with the dystrophin-dystrobrevin subcomplex through extensive interaction with the ZZ domain of dystrophin. Collectively, these findings enhance our understanding of the structural linkage across the cell membrane and provide a foundation for the molecular interpretation of many muscular dystrophy-related mutations.

DOI: https://doi.org/10.1038/s41586-024-08310-2
Function (Oxf). 2024 Dec 10. pii: zqae053. [Epub ahead of print]

The core circadian clock factor, Bmal1, transduces sex-specific differences in both rhythmic and non-rhythmic gene expression in the mouse heart.

Xiping Zhang, Spencer B Procopio, Haocheng Ding, Maya G Semel, Elizabeth A Schroder, Mark R Viggars, Tanya S Seward, Ping Du, Kevin Wu, Sidney R Johnson, Abhilash Prabhat, David J Schneider, Isabel G Stumpf, Ezekiel R Rozmus, Zhiguang Huo, Brian P Delisle, Karyn A Esser.

  It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However, little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice. Here, we show that the core clock genes are expressed in common in both sexes, but the cardiac circadian transcriptome is very sex specific. Hearts from female mice expressed significantly more rhythmically expressed genes (REGs) than male hearts, and the temporal distribution of REGs was distinctly different between sexes. To test the contribution of the circadian clock in sex-specific gene expression in the heart, we knocked out the core circadian clock factor Bmal1 in adult cardiomyocytes. The sex differences in the circadian transcriptomes were significantly diminished with cardiomyocyte-specific loss of Bmal1. Surprisingly, loss of cardiomyocyte Bmal1 also resulted in a roughly 8-fold reduction in the number of all differentially expressed genes (DEGs) between male and female hearts. We highlight sex-specific changes in several cardiac-specific transcription factors, including Gata4, Nkx2-5 and Tbx5. While there is still much to learn, we conclude that cardiomyocyte-specific Bmal1 is vital in conferring sex-specific gene expression in the adult mouse heart.

Keywords:  brain and muscle ARNT-like 1; cardiomyocyte; circadian rhythms; sex differences

DOI:  https://doi.org/10.1093/function/zqae053
Scand J Med Sci Sports. 2024 Dec;34(12): e70000

Honoring Bengt Saltin: A Decade of Reflection on His Legacy in Exercise Physiology.

Hans-Christer Holmberg.



Keywords:  Bengt Saltin; circulatory regulation; cross‐country skiing; exercise physiology; human performance; integrative physiology; muscle metabolism; sports science

DOI:  https://doi.org/10.1111/sms.70000
Nat Aging. 2024 Dec;4(12): 1657

Reproductive aging research as a gateway to health and wellbeing.

DOI: https://doi.org/10.1038/s43587-024-00786-x