Methylome-proteome integration after late-life voluntary exercise training reveals regulation and target information for improved skeletal muscle health.

Autor: Chambers TL; Exercise Science Research Center, Molecular Muscle Mass Regulation Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, USA., Dimet-Wiley A; Ridgeline Therapeutics, Houston, TX, USA., Keeble AR; University of Kentucky Center for Muscle Biology, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Haghani A; Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA.; Altos Labs, San Diego, CA, USA., Lo WJ; Department of Educational Statistics and Research Methods, University of Arkansas, Fayetteville, AR, USA., Kang G; University of Kentucky Center for Muscle Biology, Lexington, KY, USA.; Department of Physiology, University of Kentucky, Lexington, KY, USA.; Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky, Lexington, KY, USA., Brooke R; Epigenetic Clock Development Foundation, Los Angeles, CA, USA., Horvath S; Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA.; Altos Labs, San Diego, CA, USA.; Epigenetic Clock Development Foundation, Los Angeles, CA, USA., Fry CS; University of Kentucky Center for Muscle Biology, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Watowich SJ; Ridgeline Therapeutics, Houston, TX, USA.; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA., Wen Y; University of Kentucky Center for Muscle Biology, Lexington, KY, USA.; Department of Physiology, University of Kentucky, Lexington, KY, USA.; Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky, Lexington, KY, USA., Murach KA; Exercise Science Research Center, Molecular Muscle Mass Regulation Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, USA.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2024 Jul 26. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1113/JP286681
Abstrakt: Exercise is a potent stimulus for combatting skeletal muscle ageing. To study the effects of exercise on muscle in a preclinical setting, we developed a combined endurance-resistance training stimulus for mice called progressive weighted wheel running (PoWeR). PoWeR improves molecular, biochemical, cellular and functional characteristics of skeletal muscle and promotes aspects of partial epigenetic reprogramming when performed late in life (22-24 months of age). In this investigation, we leveraged pan-mammalian DNA methylome arrays and tandem mass-spectrometry proteomics in skeletal muscle to provide detailed information on late-life PoWeR adaptations in female mice relative to age-matched sedentary controls (n = 7-10 per group). Differential CpG methylation at conserved promoter sites was related to transcriptional regulation genes as well as Nr4a3, Hes1 and Hox genes after PoWeR. Using a holistic method of -omics integration called binding and expression target analysis (BETA), methylome changes were associated with upregulated proteins related to global and mitochondrial translation after PoWeR (P = 0.03). Specifically, BETA implicated methylation control of ribosomal, mitoribosomal, and mitochondrial complex I protein abundance after training. DNA methylation may also influence LACTB, MIB1 and UBR4 protein induction with exercise - all are mechanistically linked to muscle health. Computational cistrome analysis predicted several transcription factors including MYC as regulators of the exercise trained methylome-proteome landscape, corroborating prior late-life PoWeR transcriptome data. Correlating the proteome to muscle mass and fatigue resistance revealed positive relationships with VPS13A and NPL levels, respectively. Our findings expose differential epigenetic and proteomic adaptations associated with translational regulation after PoWeR that could influence skeletal muscle mass and function in aged mice. KEY POINTS: Late-life combined endurance-resistance exercise training from 22-24 months of age in mice is shown to improve molecular, biochemical, cellular and in vivo functional characteristics of skeletal muscle and promote aspects of partial epigenetic reprogramming and epigenetic age mitigation. Integration of DNA CpG 36k methylation arrays using conserved sites (which also contain methylation ageing clock sites) with exploratory proteomics in skeletal muscle extends our prior work and reveals coordinated and widespread regulation of ribosomal, translation initiation, mitochondrial ribosomal (mitoribosomal) and complex I proteins after combined voluntary exercise training in a sizeable cohort of female mice (n = 7-10 per group and analysis). Multi-omics integration predicted epigenetic regulation of serine β-lactamase-like protein (LACTB - linked to tumour resistance in muscle), mind bomb 1 (MIB1 - linked to satellite cell and type 2 fibre maintenance) and ubiquitin protein ligase E3 component N-recognin 4 (UBR4 - linked to muscle protein quality control) after training. Computational cistrome analysis identified MYC as a regulator of the late-life training proteome, in agreement with prior transcriptional analyses. Vacuolar protein sorting 13 homolog A (VPS13A) was positively correlated to muscle mass, and the glycoprotein/glycolipid associated sialylation enzyme N-acetylneuraminate pyruvate lyase (NPL) was associated to in vivo muscle fatigue resistance.
(© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
Databáze: MEDLINE
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