bims-moremu 2025-08-24 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–08–24
twenty-one papers selected by
Anna Vainshtein, Craft Science Inc.

Satellite Cells in Regeneration and Disease.
The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice.
RNA signaling in skeletal muscle: the central role of microRNAs and exosomal microRNAs.
Unconventional myosin VI is involved in regulation of muscle energy metabolism.
Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.
Global proteomics reveals distinct muscle adaptations to menstrual cycle phase-based sprint interval training in endurance-trained females.
Optimizing the methodology for precise estimation of skeletal muscle fiber type proportions in humans.
Muscle-specific atrophy of the lower limb musculature in responseto simulated microgravity exposure in women.
Tomatidine Attenuates Inflammatory Responses to Exercise-Like Stimulation in Donor-derived Skeletal Muscle Myobundles.
Muscle preservation during hospitalization: energy balance, protein intake, and habitual physical activity.
Gut microbiota-mediated betaine regulates skeletal muscle fiber type transition by affecting m6A RNA methylation and Myh7 expression.
Paradigm shifts: how electrical stimulation opened up new avenues in science and medicine.
Lactoferricin enables adenovirus infection of human skeletal muscle cells.
Divergent Strength Gains but Similar Hypertrophy After Low-Load and High-Load Resistance Exercise Training in Trained Individuals: Many Roads Lead to Rome.
Stopping muscle contractions and relaxations during action inhibition involves global and targeted control dependent on muscle state.
DAXX-dependent H3.3 deposition maintains myoblast cell identity independently of other histone chaperone complexes.
Effects of resistance-based training and polyphenol supplementation on physical function, metabolism, and inflammation in aging individuals.
AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria.
The effect of rotenone contamination on high-resolution mitochondrial respiration experiments.
Estimating vastus lateralis muscle volume from a single ultrasound image.
Metabolic Messenger: growth differentiation factor 15.

Cold Spring Harb Perspect Biol. 2025 Aug 18. pii: a041474. [Epub ahead of print]

Satellite Cells in Regeneration and Disease.

Marie E Esper, John Saber, Michael A Rudnicki.

Skeletal muscle owes its plasticity and ability to regenerate following severe injury to the resident somatic stem cells, termed satellite cells, of which a subset represent multipotent muscle stem cells (MuSCs). Adult MuSCs originate from mesoderm-derived somitic cells during embryonic development and are necessary for the maintenance and regeneration of skeletal muscle throughout life. In adult muscle, MuSCs reside under the basal lamina where extrinsic cues modulate their quiescence in resting conditions and activation in response to injury. The process of MuSC activation is highly regulated by the niche microenvironment, and perturbations that impact the MuSC-niche interaction can have deleterious effects on muscle regeneration. Here, we discuss the embryonic origin of skeletal muscle and MuSCs; the regulation of MuSC activation, self-renewal, and commitment; and myopathies that impact MuSC function.

DOI: https://doi.org/10.1101/cshperspect.a041474
PLoS Genet. 2025 Aug;21(8): e1011806

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

Soomin Cho, Emilia Servián-Morilla, Victoria Navarro, 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 limb-girdle muscular dystrophy (LGMDR21) 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 loss of quiescence and 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 LGMDR21.

DOI: https://doi.org/10.1371/journal.pgen.1011806
Front Cell Dev Biol. 2025 ;13 1639123

RNA signaling in skeletal muscle: the central role of microRNAs and exosomal microRNAs.

Shunshun Liu, Huan Dong.

  Skeletal muscle development and adaptation are governed by complex regulatory networks that coordinate gene expression, signaling pathways, and intercellular communication. Among the emerging key regulators are microRNAs (miRNAs) and exosomal microRNAs, which function as critical modulators of skeletal muscle growth, differentiation, regeneration, and metabolic adaptation. The review explores the acknowledged contributions of miRNAs, both intracellular and those encapsulated within exosomes, to the regulation of skeletal muscle physiology. We highlight their involvement in major molecular pathways, including PI3K/Akt/mTOR, TGF-β/Smad, Wnt/β-catenin, and AMPK signaling, and their impact on processes such as myogenesis, hypertrophy, atrophy, and mitochondrial function. Emphasis is placed on the critical role of exosomal miRNAs in orchestrating signaling pathways that enable communication among cells in the muscle milieu and with peripheral tissues. Ultimately, the review addresses the clinical relevance of miRNAs, including those derived from exosomes, emphasizing their prospective roles as diagnostic tools and intervention points in muscle-related conditions. In sum, the review elucidates the broad landscape of RNA-related regulatory processes in skeletal muscle and projects forward-looking strategies for translational exploration in this rapidly developing scientific domain.

Keywords:  aging; epigentic; exosome; microRNA; skeletal muscle

DOI:  https://doi.org/10.3389/fcell.2025.1639123
Am J Physiol Cell Physiol. 2025 Aug 18.

Unconventional myosin VI is involved in regulation of muscle energy metabolism.

Dominika Wojton, Dorota Dymkowska, Damian Matysniak, Malgorzata Topolewska, Maria Jolanta Rędowicz, Lilya Lehka.

  Mitochondria are essential for the regulation of the metabolic state of skeletal muscle, making their structure and function crucial for muscle performance. Myosin VI (MVI), an unconventional minus-end-directed motor, is expressed in skeletal muscle and myogenic cells. To explore its role in mitochondrial function and muscle metabolism, we used MVI knockout mice (Snell's waltzer, SV, MVI-KO) and their heterozygous littermates. We analyzed muscle samples from newborn (P0) and adult mice (3- and 12-months-old) and found that both MVI mRNA and protein levels were highest in newborn muscles and decreased with age. MVI expression also varied by muscle type, being highest in the slow-twitch soleus muscle (SOL) of adult mice. Loss of MVI had the most significant effects on SOL, which contains the highest number of mitochondria compared to fast-twitch muscles. MVI loss resulted in reduced respiratory capacity and ATP production in myogenic cells, indicating impaired mitochondrial function. Furthermore, MVI deficiency caused a shift from glycolytic to oxidative fiber types, especially in SOL. We also observed increased phospho-AMPK levels in MVI-KO SOL across all time points, along with downregulation of the mTOR pathway and upregulation of proteins involved in lipolysis. These findings highlight MVI as a novel regulator of metabolic processes in skeletal muscle.

Keywords:  Energy metabolism; mitochondria; myogenic cell; skeletal muscle; unconventional myosin VI

DOI:  https://doi.org/10.1152/ajpcell.00300.2025
J Biomed Sci. 2025 Aug 19. 32(1): 77

Activation of mitophagy and proteasomal degradation confers resistance to developmental defects in postnatal skeletal muscle.

Fasih A Rahman, Mackenzie Q Graham, Alex Truong, Joe Quadrilatero.

   BACKGROUND: Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
METHODS: We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7f/f:Acta1-Cre) mice.
RESULTS: Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
CONCLUSION: These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.

Keywords:  Apoptosis; Autophagy; BNIP3; Development; Mitochondria; Mitophagy; Skeletal muscle; UPS

DOI:  https://doi.org/10.1186/s12929-025-01153-7
Mol Cell Proteomics. 2025 Aug 14. pii: S1535-9476(25)00152-5. [Epub ahead of print] 101053

Global proteomics reveals distinct muscle adaptations to menstrual cycle phase-based sprint interval training in endurance-trained females.

Julie Kissow, Kamine Julie Jacobsen, Søren Jessen, Laura Bachmann Thomsen, Júlia Prats Quesada, Jens Bangsbo, Atul Shahaji Deshmukh, Morten Hostrup.

  Advances in mass-spectrometry (MS)-based technologies have leveraged our understanding of protein-wide adaptations in human skeletal muscle in response to exercise. However, there is a lack of such data in females, particularly pertaining to already trained females and menstrual cycle phase-based sprint interval training (SIT) despite its efficacy and popularity. Here, we present a comprehensive global proteome analysis of skeletal muscle adaptations to high-frequency SIT during different menstrual cycle phases in endurance-trained females. We randomized 49 eumenorrheic females to either high-frequency SIT in the follicular (FB) or luteal phase (LB) over one menstrual cycle comprising eight sessions of 6×30-s all-out efforts. MS-proteomics, covering 4155 proteins after filtering, revealed notable differences in muscle adaptations to phase-based SIT. LB suppressed mitochondrial pathways of the tricarboxylic acid cycle and electron transport chain while enriching ribosomal complexes. Conversely, FB enriched filament organization and skeletal system development. Mitochondrial repression during LB was linked to reduced V˙O2max, whereas exercise capacity improved in FB only. Our findings show that menstrual cycle phase-based high-frequency SIT induces distinct protein-wide muscle adaptations and affects phenotype in endurance-trained eumenorrheic females. CLINICAL TRIAL REGISTRATION NUMBER: NCT04136457.

Keywords:  Athletes; Estrogen; Exercise; Female; Performance; Sex hormones

DOI:  https://doi.org/10.1016/j.mcpro.2025.101053
Sci Rep. 2025 Aug 16. 15(1): 30006

Optimizing the methodology for precise estimation of skeletal muscle fiber type proportions in humans.

Nathan Serrano, Matthew R Buras, Lori R Roust, Eleanna De Filippis, Christos S Katsanos.

  Isolating individual muscle fibers and characterizing their myosin heavy chain (MHC) content using SDS-PAGE has become an increasingly common method for describing skeletal muscle fiber type proportions. In this study, we aimed to assess how the number of muscle fibers analyzed, and whether they are characterized in the order of isolation or randomly selected from a larger pool of muscle fibers, affects the precision of fiber type proportion estimates. A total of 170 individual muscle fibers were isolated from vastus lateralis biopsies from each of eight human subjects, and their MHC isoform content was analyzed using SDS-PAGE. To evaluate the precision of fiber type proportion estimates, we employed a resampling approach, varying both the muscle fiber sample size (25, 50, or 100 fibers) and the selection method (ordered vs. random selection). Our results indicate that when analyzing a small number of muscle fibers, precision improves if the fibers are randomly selected from a larger pool rather than characterized in the order they were isolated. These findings have important implications for designing experiments to assess skeletal muscle fiber heterogeneity and its role in health and disease.

Keywords:  Accuracy; Muscle fibers; Muscle phenotype; Myosin heavy chain; Number of fibers; Selection of fibers

DOI:  https://doi.org/10.1038/s41598-025-15163-w
J Appl Physiol (1985). 2025 Aug 19.

Muscle-specific atrophy of the lower limb musculature in responseto simulated microgravity exposure in women.

Kaitlyn Rogers, Gilhyeon Yoon, Caroline S Vincenty, Scott Trappe, Todd A Trappe.

  Despite the increased involvement of women in spaceflight missions, the efforts to understand changes in skeletal muscle health in women with microgravity exposure have been limited. The goal of the current investigation was to expand the limited knowledge on skeletal muscle atrophy responses to microgravity in women. Eight women (34±4y) underwent 60 days of simulated microgravity (6° head-down tilt bedrest), and changes in MRI-determined skeletal muscle volume of 17 lower limb muscles were determined after one and two months. Muscle volume decreased (p<0.05) in all 17 muscles of the women after one and two months of simulated microgravity. There was nearly a threefold difference between the least (rectus femoris: -10%) and most (soleus: -27%, lateral gastrocnemius: -28%, medial gastrocnemius: - 29%) affected muscles. Muscle-specific atrophy was also evident within muscle groups of the knee extensors (rectus femoris: -10%; vastii: -22%, p<0.05) and knee flexors (semimembranosus and biceps femoris long head: -20%; gracilis, biceps femoris short head, semitendinosus: -12%, p<0.05). These findings in women were also compared to data from men (33±7y) who previously underwent similar MRI volume determinations of the same 17 muscles after one and two months of simulated microgravity exposure. Compared to men, women experienced more pronounced atrophy in 16 of the 17 muscles (p<0.05), and at least double the atrophy in seven of these muscles. The current findings extend our understanding of the magnitude of muscle- and sex-specific skeletal muscle responses to long duration microgravity, which should be considered for spaceflight exercise countermeasures program evolution.

Keywords:  microgravity; skeletal muscle; women

DOI:  https://doi.org/10.1152/japplphysiol.00483.2025
Med Res Arch. 2025 Apr;pii: 6423. [Epub ahead of print]13(4):

Tomatidine Attenuates Inflammatory Responses to Exercise-Like Stimulation in Donor-derived Skeletal Muscle Myobundles.

Maddalena Parafati, Tushar Sanjay Shenoy, Zon Thwin, Mauro Parlavecchio, Siobhan Malany.

  Donor-derived myotubes offer a pre-clinical model for studying muscle biology, the effects of exercise-like electrical stimulation, and assessing drug efficacy and toxicity. We engineered a 3D muscle microphysiological system from myoblasts isolated from vastus lateralis of young and older adults. Over a three-week differentiation process, we applied two cycles of low frequency electrical stimulation daily for seven days generating functional, mature myobundles, as confirmed by gene expression profiling. Both young- and old-derived myobundles showed synchronous contraction in response to electrical stimulation, however, the contraction magnitude was reduced in old-derived myobundles compared to young-derived myobundles. We then assessed the donor-specific response to tomatidine, a steroidal alkaloid found in the skin of green tomatoes, known to inhibit muscle atrophy and promote skeletal muscle hypertrophy. Bioinformatic analyses revealed that infusion of tomatidine during electrical stimulation modulated the IL-6/JAK/STAT3 pathway. The contraction magnitude decreased in the young-derived myobundles treated with tomatidine compared to vehicle-treated controls, while no significant difference was observed in the old-derived myobundles. Secretome analysis revealed age-related changes in secreted proteins linked to inflammation and extracellular matrix remodeling. Notably, tomatidine attenuates the inflammatory and extracellular matrix remodeling responses in the myobundles triggered by electrical stimulation, partially preventing the secretion of proinflammatory proteins. This intervention strategy helps balance muscle adaptation and repair, while limiting excessive proinflammatory responses. Our microphysiological system provides a valuable platform for investigating signaling pathways involved in muscle function, and pharmacological responses, advancing the understanding of age-related muscle biology.

Keywords:  E-Stim-induced contraction; donor-derived myobundles; inflammation; muscle-on-a-chip; secretome; tomatidine; transcriptome

DOI:  https://doi.org/10.18103/mra.v13i4.6423
Curr Opin Clin Nutr Metab Care. 2025 Aug 01.

Muscle preservation during hospitalization: energy balance, protein intake, and habitual physical activity.

Cas J Fuchs, Luc J C van Loon.

   PURPOSE OF REVIEW: Muscle loss during hospitalization is a major clinical concern, as it has been associated with reduced physical function, quality of life, and increased mortality. This review outlines the key causes of muscle wasting and highlights practical strategies to support muscle mass preservation during hospitalization.
RECENT FINDINGS: Physical inactivity, along with reduced energy and protein intake, are the primary drivers of muscle atrophy during hospitalization by suppressing muscle protein synthesis (MPS). Maintaining energy balance is critical to prevent declines in MPS rates and attenuate muscle loss. Preserving habitual protein intake is essential and, when total energy intake is reduced, should be achieved through a more protein-dense diet. Preventing disuse atrophy requires at least some level of daily physical activity. Physical activity sensitizes skeletal muscle to the anabolic properties of protein ingestion, enabling greater use of protein-derived amino acids for MPS. Therefore, frequent in-hospital movements, such as bed-to-chair transfers and walking, should be encouraged. When voluntary activity or muscle contractions are impossible, exercise mimetics, like neuromuscular electrical stimulation, may be applied to stimulate muscle activity and limit muscle mass loss.
SUMMARY: Preserving muscle mass during hospitalization requires a multimodal approach: achieving energy balance, maintaining protein intake, minimizing muscle disuse, and, whenever necessary, apply exercise mimetics.

Keywords:  bed rest; exercise mimetics; muscle atrophy; muscle mass; muscle protein synthesis

DOI:  https://doi.org/10.1097/MCO.0000000000001154
Gut Microbes. 2025 Dec;17(1): 2545434

Gut microbiota-mediated betaine regulates skeletal muscle fiber type transition by affecting m6A RNA methylation and Myh7 expression.

Chao Yan, Yilong Yao, Zhaobo Zhang, Fanqinyu Li, Danyang Fan, Wen Liu, Xinhao Fan, Lingna Xu, Yanwen Liu, Shilong Wang, Mengling Hu, Yalan Yang, Zhonglin Tang.

  Skeletal muscle fiber composition is essential for maintaining muscle function and overall health. Growing evidence underscores the pivotal role of the gut-muscle axis in mediating the influence of gut microbiota on skeletal muscle development. However, the mechanisms underlying microbiota-mediated regulation of skeletal muscle fiber type remain unclear. Here, we employed multi-omics approaches, including RNA-seq, MeRIP-seq, 16S rRNA gene sequencing, and metabolomics, to investigate the causal relationship between the gut microbiota and skeletal muscle fiber transition. Our results demonstrate that the gut microbiota modulates skeletal muscle fiber transition by influencing N6-methyladenosine (m6A) methylation to regulate the expression of the slow-twitch fiber marker Myh7. Specifically, METTL3-dependent m6A methylation enhances Myh7 gene expression, leading to an increased proportion of slow-twitch fibers and a reduction in fast-twitch fibers. Furthermore, the microbiota-derived methyl donor betaine promotes Myh7 expression and Akkermansia muciniphila (AKK) abundance, and facilitates fast-to-slow fiber conversion via m6A modification. The transplantation of AKK significantly altered betaine levels and m6A modification, thereby promoting muscle fiber remodeling. In conclusion, these findings reveal that AKK-coordinated betaine drives skeletal muscle fiber conversion by modulating Myh7 mRNA expression. This study provides novel insights into the role of m6A RNA methylation in the gut-muscle crosstalk, highlighting potential therapeutic targets for muscle-related disorders.

Keywords:  Betaine; Myh7; gut microbiota; m6A RNA methylation; myofiber-type transition

DOI:  https://doi.org/10.1080/19490976.2025.2545434
Eur J Transl Myol. 2025 Aug 06.

Paradigm shifts: how electrical stimulation opened up new avenues in science and medicine.

Stanley Salmons.

The discovery that skeletal muscle can respond adaptively to use, even to the extent of re-expressing its genome, overturned two paradigms and led to new insights into gene regulation and a variety of clinical applications.

DOI: https://doi.org/10.4081/ejtm.2025.14058
Npj Viruses. 2025 Aug 19. 3(1): 62

Lactoferricin enables adenovirus infection of human skeletal muscle cells.

Katarina Danskog, Nitesh Mistry, Carin Årdahl, Madeleine Durbeej, Mattias N E Forsell, Annasara Lenman, Niklas Arnberg.

Although adenoviruses (AdVs) possess advantageous features as vectors, several challenges remain. These include a high prevalence of neutralizing antibodies against certain AdV types and the inability to efficiently transduce CAR-deficient cells and tissues. We showed previously that lactoferricin (Lfcin) enhances CAR-independent HAdV-C5 infection of epithelial and T-cells. Here, we assessed the ability of Lfcin to enable HAdV-C5 infection and transduction of human skeletal muscle cells. Lfcin increases HAdV-C5 infection and transduction of muscle myoblasts and myotubes by 10- to 30-fold. Enhanced infection correlates with increased cell binding, which differs mechanistically from that of coagulation factor X-mediated binding, as it remains unaffected by the removal of heparan sulfate. Additionally, Lfcin reduces the neutralizing effects of serum against HAdV-C5, suggesting it may shield key epitopes. By enabling viral binding to muscle cells and mitigating serum neutralization, Lfcin offers a novel strategy to improve the efficiency and durability of HAdV-C5-based gene delivery systems.

DOI: https://doi.org/10.1038/s44298-025-00144-7
J Appl Physiol (1985). 2025 Aug 19.

Divergent Strength Gains but Similar Hypertrophy After Low-Load and High-Load Resistance Exercise Training in Trained Individuals: Many Roads Lead to Rome.

Kristoffer Toldnes Cumming, Ingrid Cecelia Elvatun, Richard Kalenius, Gordan Divljak, Truls Raastad, Niklas Psilander, Oscar Horwath.

  The muscular and myocellular adaptations to low-load resistance exercise training (LL-RET) remain incompletely understood in the trained state. The primary aim of this study was to examine adaptations to an LL-RET regimen, comparing these to a high-load training regimen (HL-RET). Fourteen resistance-trained males and females (26.4 ± 4.4 years) participated in a 9-week RET program (twice per week). Using a within-subject design, each individual trained one leg with HL-RET (3-5 repetitions), and the other with LL-RET (20-25 repetitions), all sets performed to volitional failure. Maximal strength (1 RM) and muscle thickness were assessed. Muscle biopsies were analyzed for fiber type composition, fiber cross-sectional area (fCSA), and satellite cell- and myonuclear content using immunofluorescence. The training regimens led to comparable increases in 1 RM in multi-joint movements (21 ± 10%), but not in single-joint movements where HL-RET was superior (9 ± 13% vs -3 ± 10%). Regardless of training regimen, muscle thickness increased pre- to post-intervention by 7 ± 17% at the mid-thigh site and 8 ± 8% at the distal site. However, this was not accompanied by changes at the myocellular level, with no observed differences in fCSA and fiber type composition. Satellite cell content increased by 25 ± 57% in type I fibers, independent of training regimen, but no changes were noted in myonuclear content. LL-RET can replicate many aspects of HL-RET leading to similar increases in muscle hypertrophy and strength. Our study supports the notion that comparable adaptations to RET can be achieved using widely distinct loading regimens.

Keywords:  PCM1; Pax7; human muscle fibers; myonuclei; weightlifting

DOI:  https://doi.org/10.1152/japplphysiol.00353.2025
J Neurosci. 2025 Aug 19. pii: e1170252025. [Epub ahead of print]

Stopping muscle contractions and relaxations during action inhibition involves global and targeted control dependent on muscle state.

Jack De Havas, Jaime Ibañez, Hiroaki Gomi, Sven Bestmann.

The mechanisms underpinning the stopping of muscle contractions and relaxations during action inhibition remain unclear. Central stop commands may be targeted and act on task-active muscles only, or instead be global, acting on task-passive muscles as well. We addressed this question in three stop signal task experiments with human participants (n=54; 18 Male, 36 Female). Whilst maintaining baseline force levels (10% MVC) in both index fingers, Go signals required participants to increase or decrease this force in the task-active finger (Task-active Contract vs Task-active Relax) while keeping activity in the task-passive muscle constant. On 30% of trials, delayed stop signals instructed participants to stop the task-active responses. Stop-related activity was detected in task-active muscles at the single trial-level, using electromyography (EMG), and used to determine whether stop-related activity was also present in task-passive muscles. We found that stop commands act on both task-active and task-passive muscles, suggesting global control. This global control was furthermore muscle-state specific, by decreasing muscle activity when stopping contractions, and increasing muscle activity when stopping relaxations. However, stopping muscle contractions involved more sustained suppression of muscle activity in task-active than task-passive muscles, suggesting additional targeted control. This was not the case when stopping muscle relaxations, which only showed evidence of global control. Our results may explain how complex, real-world actions are inhibited. Global stop commands that are sensitive to muscle state may rapidly adjust muscle activity across the body, with additional control targeted to contracting, task-active muscles.Significance statement The nature of stop commands sent to the muscles during action inhibition was unclear. We show that action inhibition changes activity in task-passive as well as task-active muscles, suggesting that stop commands are global in nature. Global stop commands were muscle-state specific; they decreased activity when stopping contracting muscles and increased it when stopping relaxing muscles. Evidence for additional targeted commands being sent to task-active muscles (i.e. more sustained suppression than task-passive muscles) was only found when stopping muscle contractions, not when stopping relaxations. Action inhibition may therefore be underpinned by global stop commands that decrease and increase motor output according to whether muscles are contracting or relaxing, with additional targeted commands being sent to suppress contracting, task-active muscles.

DOI: https://doi.org/10.1523/JNEUROSCI.1170-25.2025
iScience. 2025 Aug 15. 28(8): 113119

DAXX-dependent H3.3 deposition maintains myoblast cell identity independently of other histone chaperone complexes.

Virginia Zoglio, Sarah Chebouti, Fayez Issa, Frédéric Relaix, Joana Esteves de Lima.

  H3.3 histone chaperone DAXX regulates heterochromatin silencing; however, its function in transcription regulation remains understudied. Here, we show that Daxx knockout (KO) myoblasts have impaired differentiation and fusion. Transcriptomic analysis revealed a loss in myogenic gene expression and broad transcription dysregulation in Daxx KO myoblasts. Chromatin immunoprecipitation followed by sequencing demonstrated a marked reduction in H3.3 deposition at myogenic loci in Daxx KO myoblasts, which was further linked to decreased H3K27ac. Intriguingly, the double KO of Daxx and Hira resulted in distinct transcriptomic alterations than those of single KOs, demonstrating that DAXX and HIRA have both overlapping and unique roles in H3.3 incorporation. Our findings establish DAXX as a critical regulator of myogenic gene expression and muscle cell identity through a distinct mechanism from that of HIRA and highlighted an unanticipated plasticity in the deposition loci for DAXX and HIRA in myoblasts.

Keywords:  cell biology; transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.113119
Geroscience. 2025 Aug 19.

Effects of resistance-based training and polyphenol supplementation on physical function, metabolism, and inflammation in aging individuals.

Mathias Flensted-Jensen, Cecilie Moe Weinreich, Ann-Sofie Kleis-Olsen, Filip Hansen, Nadia Stenner Skyggelund, Jeppe Rahbek Pii, Ryan Whitlock, Marie-Louise Brødsgaard Abrahamsen, Thomas Isbrandt Petersen, Anders Karlsen, Dace Reihmane, Flemming Dela.

  Aging is associated with declines in muscle mass, strength, aerobic capacity, and metabolic health, accompanied by increased low-grade inflammation. The purpose of this study was to assess the effects of 12 weeks of resistance training (RT) combined with minimal high-intensity interval training (HIIT), with or without polyphenol supplementation, on muscular, cardiovascular, metabolic, and inflammatory adaptations in healthy older adults. Forty-one men and women aged 55-70 years ingested either polyphenol supplementation or placebo for 30 days, then underwent 12 weeks of supervised RT combined with once-weekly HIIT, continuing polyphenol supplementation or placebo throughout. The training intervention increased whole-body and thigh lean mass, vastus lateralis cross-sectional area, type II fiber size, and muscle and functional strength (all p < 0.001). Maximal oxygen uptake significantly increased (p = 0.0001), accompanied by reductions in heart rate and plasma lactate during submaximal exercise, as well as increases in total blood volume and hemoglobin mass (p < 0.05). Training led to reductions in respiratory exchange ratio and plasma cortisol during exercise, which, together with decreased cholesterol levels and trends toward increased peak fat oxidation, may suggest enhanced substrate utilization. Polyphenols alone lowered cholesterol levels but had no other effects. Although no changes were observed in basal systemic or muscle inflammation, the exercise intervention attenuated the acute exercise-induced inflammatory responses of IL-10, IFN-γ, and TNF-α (p < 0.05). These results indicate that a combined RT and minimal HIIT program improves muscular, aerobic, and metabolic health, and may improve inflammatory regulation in aging adults.

Keywords:  Aging; Exercise; Inflammation; Polyphenols; Resistance training

DOI:  https://doi.org/10.1007/s11357-025-01839-8
Cell Death Dis. 2025 Aug 18. 16(1): 623

AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria.

Lupeng Chen, Yue Liu, Junzhi Zhang, Tongxing Song, Jian Wu, Zhuqing Ren.

Lipid droplet (LD) -mitochondrion contacts play a crucial role in regulating energy metabolism and fatty acid oxidation in skeletal muscle cells. However, the proteins that regulate these interactions remain poorly understood. Here, we demonstrate that the binding between ADP-ribosylation factor 1(ARF1) and perilipin2 (Plin2) regulates LD-mitochondrion contacts under starvation conditions, facilitating the transfer of fatty acids from LDs to mitochondria. In C2C12 cells, starvation increased ARF1's GTP-binding activity and its localization to mitochondria, enhancing ARF1's binding to Plin2 and facilitating fatty acid flow from LDs to mitochondria. In contrast, knockdown of ARF1 reduced LD-mitochondrion interactions and blocked fatty acids transfer. Additionally, ARF1-mediated interactions were regulated by AMPK; inhibiting AMPK activity reduced ARF1 localization to LDs and mitochondria, and blocked LD-mitochondrion interactions. In mice, starvation increased ARF1 expression in muscle tissue and LD-mitochondrion contacts. Conversely, inhibiting ARF1 led to lipid accumulation in muscle tissue. In conclusion, our work suggests that ARF1 is a critical regulator of LD-mitochondrion interactions and plays a significant role in energy metabolism regulation in skeletal muscle.

DOI: https://doi.org/10.1038/s41419-025-07957-7
PeerJ. 2025 ;13 e19879

The effect of rotenone contamination on high-resolution mitochondrial respiration experiments.

Dale F Taylor, Jia Li, Nicholas J Saner, Jia Wei, Xu Yan, Elizabeth G Reisman, Hanzhe Li, Matthew J-C Lee, Navabeh Zare, Andrew Garnham, Jujiao Kuang, David J Bishop.

   Background: High-resolution respirometry is commonly used in skeletal muscle research and exercise science to measure mitochondrial respiratory function in both permeabilized muscle fibers and isolated mitochondria. Due to the low throughput and high cost of the most used respirometer, the Oroboros 2k (O2k), multiple experiments are often conducted within the same chamber in short succession. Despite this, no methodological consideration has been given for the potential contamination of inhibitors, used to investigate the contribution of specific complexes within the electron transport chain, between experiments.
Methods: We first assessed the potential effect of inhibitor contamination on mitochondrial respiration experiments by evaluating the ability of the currently recommended wash protocol to remove rotenone and compared its efficacy against a simplified wash protocol of sequential rinses. Secondly, we assessed the potential effect of inhibitor contamination on mitochondrial respiration measured before and after a single session of high-intensity interval exercise, with and without the use of rotenone between experiments.
Results: The currently recommended protocol for washing chambers was insufficient for removing rotenone. Following exercise, a decrease in mitochondrial respiration was observed exclusively in chambers exposed to rotenone between experiments.
Discussion: Our findings highlight an important methodological consideration regarding the measurement of mitochondrial respiratory function using high-resolution respirometry, with inhibitor contamination potentially affecting the conclusions derived from experiments conducted in close succession. Future studies investigating mitochondrial respiratory function should assess the necessity of using inhibitors such as rotenone, ensure thorough wash procedures between experiments, and explicitly report the washing protocols used.

Keywords:  Bioenergetics; Exercise; Exercise-induced adaptation; Mitochondria; Oroboros O2k; Permeabilized fibers; Protocol development; Respiration; Rotenone

DOI:  https://doi.org/10.7717/peerj.19879
Sci Rep. 2025 Aug 18. 15(1): 30186

Estimating vastus lateralis muscle volume from a single ultrasound image.

Moritz Eggelbusch, Guido Weide, Michael Tieland, Renske N Vergeer, Luuk Vos, Jantine van den Helder, Stephan van der Zwaard, Richard T Jaspers, Peter J M Weijs, Rob C I Wüst.

  The assessment of skeletal muscle volume is valuable for fundamental research and clinical practice, but remains limited in larger cohorts due to its time-consuming nature. Here, we developed a method to accurately estimate vastus lateralis (VL) muscle volume based on a single measurement of anatomical cross-sectional area (ACSA) or tissue thickness. Sixty-nine healthy participants (20-91 years) volunteered. In a subgroup (n = 34) we measured VL volume and ACSAs at 10% intervals along the muscle length to derive a VL muscle shape factor. We subsequently estimated VL volume by multiplying this muscle shape factor with muscle length and a single measure of ACSA at 50% muscle length (ACSAVL50%) or an estimated ACSAVL50% from a single ultrasound scan of tissue thickness in an independent cohort (n = 35). VL muscle shape factor was determined by integrating a fourth-order polynomial of muscle length and ACSA, and was dependent on muscle size. Estimating muscle volume had a high accuracy (R²=0.976, CCC = 0.987), low bias and error (< 8.5%) in both the main cohort and an independent validation group. Estimating muscle volume from stitching 2D images at 50% muscle length or estimating ACSA with a geometric model explained 91-95% of variance in measured volumes, with high accuracy and concordance correlation coefficients. VL muscle volume can be estimated by multiplying a muscle shape factor with muscle length and ACSAVL50% from a single ultrasound image. We present a novel, cost-effective, rapid, yet accurate assessment of VL muscle mass for (large-scale) studies and clinical practice.

Keywords:  Anatomical cross-sectional area; Skeletal muscle thickness; Skeletal muscle volume; Ultrasound

DOI:  https://doi.org/10.1038/s41598-025-11437-5
Nat Metab. 2025 Aug 18.

Metabolic Messenger: growth differentiation factor 15.

Samuel N Breit, Vicky W Tsai.

Growth differentiation factor 15 (GDF15; also known as macrophage-inhibitory cytokine-1) is a stress-responsive cytokine that is overexpressed under a broad range of conditions. It has a role in regulating appetite and body weight and is an aetiological factor in anorexia-cachexia syndromes, as well as nausea and vomiting during pregnancy. Long after its original cloning, its receptor was identified as GFRAL, a distant member of the GDNF receptor family within the TGFβ superfamily, with RET as its co-receptor. Both of these are highly localized to specific hindbrain regions. Although many of GFRAL's metabolic changes may be linked to its effect on suppressing appetite, recent findings suggest that GDF15 also independently regulates energy expenditure and insulin sensitivity. Here, we review recent literature and provide updates on the current understanding of GDF15 biology and its therapeutic applications in health and metabolic diseases.

DOI: https://doi.org/10.1038/s42255-025-01353-3