Aug 2026· Cell Reports· Vol 45 8, pp.
117823
· 0 citations· 87 references
Medicine
TL;DR
It is indicated that sex-specific skeletal muscle exercise adaptations are particularly evident at the PTM level in rats, and future avenues for precision exercise health and medicine are identified.
Abstract
Exercise training confers broad health benefits, yet molecular regulators of skeletal muscle adaptation, particularly sex-specific mechanisms, remain incompletely understood. Integrating new and previously published multi-omics data from the molecular transducers of physical activity consortium (MoTrPAC), we characterized metabolomic, epigenomic, transcriptomic, proteomic, and post-translational modification (PTM) responses to 1-8 weeks of endurance exercise training in male and female rat gastrocnemius. While transcriptomic and proteomic responses were largely sex-concordant, there were distinct sex-specific training-induced PTM signatures, particularly in the redox proteome. Females exhibited decreased mitochondrial protein cysteine oxidation alongside increased oxidation of glycolytic proteins relative to males, suggesting sex-biased subcellular reactive oxygen species (ROS) dynamics. Multi-omic factor analysis (MOFA) identified coordinated sex-concordant molecular programs and further supported female-specific mechanisms of redox buffering with training. Together, these findings indicate that sex-specific skeletal muscle exercise adaptations are particularly evident at the PTM level in rats, and identify future avenues for precision exercise health and medicine.
Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery. Temporal multi-omics maps stage-specific liver adaptation to endurance training. Exercise shifts hepatic responses from transcription to metabolic remodeling. Males favor energy/redox adaptation, females favor lipids and proteostasis. Single-cell analysis links remodeling to altered cell communication, not turnover. PPP1R3G validation supports post-transcriptional control of liver adaptation.
Yuan Gao, Zhang-Yi Tu, Qi Zhao et al.· Cell Communication and Signa...· 0 citations
A spatial transcriptomic atlas of skeletal muscle from young and aged mice is presented, resolving transcriptional reprogramming across fiber types and tissue compartments and revealing alterations in sarcomeric organization, excitation-contraction coupling, oxidative stress responses, and fiber type-specific metabolic rewiring.
Veronica Ruggieri, Andrea Bracaglia, Lorenza Esposito et al.· iScience· 0 citations
Skeletal muscle aging is characterized by the deterioration of muscle function, which can lead to negative quality-of-life outcomes including frailty and sarcopenia. While understanding the mechanisms of this process is increasingly important as the global population ages, previous molecular studies of skeletal muscle aging have been limited by statistical power and cell type resolution. In this study, we analyzed single-nucleus gene expression and chromatin accessibility data from 287 human skeletal muscle samples from individuals aged 20-79 years to explore sex- and cell type-specific aging effects. Across 467,126 nuclei from 13 cell types, we identify 384 age-associated genes and 4,061 age-associated chromatin regions. These age-associated molecular features are enriched for functional pathways, including metabolic processes, cell-to-cell communication, and senescence Kyoto Encyclopedia of Genes and Genomes KEGG terms. Age-associated closing chromatin was more common across fiber types and sexes than opening chromatin, and was enriched in active enhancer regions while depleted for active transcription start sites. We observe enrichment for specific transcription factor motifs in closing chromatin, including those of glucocorticoid and androgen receptors, both of which play a key role in the maintenance of healthy skeletal muscle. Together, these findings identify an age-associated regulatory shift, largely invisible in matched transcriptomic data, characterized by closing chromatin which reduces accessibility to hormone receptor binding sites and enhancer regions in the muscle fiber epigenome.
Keagan G. Moo, Peter Orchard, A. Varshney et al.· bioRxiv· 0 citations
Cancer cachexia is characterised by progressive skeletal muscle wasting and dysfunction, yet the early events that precede overt muscle wasting remain poorly defined. Here, we utilised a time-coursed C26 carcinoma model in male and female mice to define the pre-cachectic transcriptomic, proteostatic, immune, and metabolic adaptations between sexes. Males progressed more rapidly to cachexia and exhibited earlier impairments in body composition and grip strength, with shifts in muscle fiber size distribution detectable prior to changes in muscle mass. Transcriptomic analysis of the tibialis anterior muscle identified >6,000 differentially expressed genes, with >60% showing sex-specific regulation at the pre-cachectic stage. Proteostasis pathways were transcriptionally altered in both sexes, however, global muscle protein synthesis was suppressed earlier in males, preceding both measurable muscle mass loss and robust induction of specific E3 ubiquitin ligases. Transcripts related to innate immunity were preferentially elevated in males and accompanied by increased infiltration of myeloid cells, while systemic immune profiles showed limited concordant changes. Females showed preferential enrichment of insulin resistance and metabolic remodeling pathways, accompanied by early impairment of insulin handling and reduced muscle glycogen content at severe cachexia. These results show that cachexia progression in this model is sexually dimorphic and skeletal muscle undergoes extensive remodeling before overt wasting. Males exhibit earlier functional decline and muscle immune remodeling, whereas females show earlier metabolic vulnerability with impaired insulin handling. These findings define sex-divergent pre-cachectic windows that may guide early biomarker discovery and therapeutic strategies aimed at preventing progression and improving quality of life in cancer patients.
Chris Karagiannis, Alastair A. E. Saunders, Rachel E. Thomson et al.· American Journal of Physiolo...· 0 citations
Summary Background Understanding how skeletal muscle responds to weight loss is crucial for developing targeted strategies to manage obesity and promote sustained improvement in metabolic health. Here, we investigated the molecular mechanisms underlying skeletal muscle reprogramming of gene expression and metabolic activity following Roux-en-Y gastric bypass (RYGB). Methods Forty-one women were studied before and one year after RYGB surgery. We leveraged multi-omics (DNA methylomics and transcriptomics) and machine learning approaches to complement muscle metabolic analyses and clinical data to identify mechanisms underlying RYGB-induced muscle metabolic reprogramming. Findings RYGB markedly decreased body weight and fat mass and improved metabolic health. Integrative analysis of vastus lateralis muscle identified 8233 genes with differentially methylated regions and 2173 differentially expressed genes post-RYGB surgery, of which 1197 genes were both differentially methylated and differentially expressed. Promoter hypomethylation was associated with the enhanced expression of transcription factors involved in skeletal muscle development and ribosomal subunits. In contrast, expression of genes encoding mitochondrial proteins decreased despite increases in mitochondrial content and enhanced mitochondrial function in skeletal muscle post-RYGB. Pre-operative muscle OXPHOS capacity, and expression of skeletal muscle hypertrophy and differentiation genes MYOC and EHMT2 were associated with weight loss success. Interpretation RYGB improves systemic metabolic health and induces sustained skeletal muscle bioenergetic reprogramming characterised by enhanced expression of genes involved in myogenesis and protein translation, but decreased expression of genes involved in mitochondrial metabolism, which may reflect improved mitochondrial quality and function. These findings advance our understanding of skeletal muscle metabolic responses to weight loss and of individual variability in metabolic phenotypes. Funding Canadian Institutes of Health Research (CIHR PJT183651-M-EH, 201709FDN-CEBA-116200-GRS), Diabetes Canada Investigator Award grant OG-3-22-5645-GS (GRS), J. Bruce Duncan Endowed Chair in Metabolic Diseases (GRS), Tier 1 Canada Research Chair in Mitochondrial Bioenergetics and Metabolic Health (M-EH), Tier 1 Canada Research Chair in Metabolic Diseases (GRS).
Chantal A. Pileggi, Dhanuddara Mohottalage, Luke S. Kennedy et al.· EBioMedicine· 0 citations
Abstract Skeletal muscle atrophy is a secondary complication in the aetiology of injury and chronic disease. Identifying mechanisms that control muscle mass is necessary to characterise atrophy and develop prevention strategies. We aimed to integrate transcriptomic and epigenomic data to identify key regulatory pathways controlled by promoter DNA methylation during muscle unloading. Twenty‐one healthy men (20–40 years) completed a 4‐week standardised exercise programme prior to a 14‐day knee brace immobilisation with dietary control. Skeletal muscle mass and strength were assessed before and after immobilisation and biopsies were collected (m. vastus lateralis) before, at 3 days, and at completion at 14 days. RNA and DNA were isolated and analysed using Illumina RNA sequencing and DNA methylation 850K EPIC BeadChips. The 14‐day immobilisation decreased muscle mass (∼9%; P < 0.0001) and strength (∼16%; P < 0.0001). At 3 days, most biological processes (BPs) were upregulated/hypomethylated (157 gene sets); upregulated BPs included cell signalling and protein ubiquitination and downregulated BPs included metabolism. After 14 days, BPs were predominantly downregulated/hypermethylated, including translation and ribosome biogenesis. Across both time points, HDAC4, GADD45A and CHRNA1 emerged as methylation‐regulated candidate mediators of atrophy. HDAC4 and GADD45A showed strong correlations primarily at day 3, and CHRNA1 remained significant at both time points, extending prior observations in animals to human skeletal muscle. We have characterised changes in gene expression related to hypo‐ and hyper‐methylation during muscle unloading in humans. These data extend our understanding of the regulatory processes that occur during skeletal muscle atrophy that, at the individual gene level, may be useful in developing strategies for reducing muscle wasting.
Jamie-Lee M. Thompson, Thomas M Doering, B. Budiono et al.· Experimental Physiology· 0 citations
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