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Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from (1) a skeletal muscle‐specific in vivo Oct3/4, Klf4, Sox2 and Myc (OKSM) reprogramming‐factor expression murine model; (2) an in vivo inducible muscle‐specific Myc induction murine model; (3) a translatable high‐volume hypertrophic exercise training approach in aged mice; and (4) human exercise muscle biopsies, we collectively defined exercise‐induced genes that are common to partial reprogramming. Late‐life exercise training lowered murine DNA methylation age according to several contemporary muscle‐specific clocks. A comparison of the murine soleus transcriptome after late‐life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle‐enriched genes was conserved in skeletal muscle of long‐term exercise‐trained humans; among these was muscle‐specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC‐controlled and exercise adaptation transcriptomes, including lower muscle‐specific Melusin and reactive oxygen species‐associated Romo1. With Myc, OKSM and exercise training in mice, as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. Key points: Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodelling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2 and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing.Using global gene expression analysis, we compared the effects of in vivo OKSM‐mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late‐life murine exercise training in muscle.Myc is the Yamanaka factor most induced by exercise in skeletal muscle, and so we compared the MYC‐controlled transcriptome in muscle to Yamanaka factor‐mediated and exercise adaptation mRNA landscapes in mice and humans.A single pulse of MYC is sufficient to remodel the muscle methylome.We identify partial reprogramming‐associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses. [ABSTRACT FROM AUTHOR]

Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole‐body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi‐weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7‐ or 28 days prior to euthanization. Senescence‐associated β‐Galactosidase positive (SA β‐Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β‐Gal+ cells were also CD11b+ in young and old mice 7‐ and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β‐Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti‐inflammatory macrophages. SA β‐Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q‐treated old mice, muscle regenerated following injury to a greater extent compared to vehicle‐treated old mice, having larger fiber cross‐sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice. [ABSTRACT FROM AUTHOR]

Key points: Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery.A PCR‐based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE.Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non‐canonical MYC‐associated regions, but not the promoter.Myonuclear‐specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans.A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage. Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise‐induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 ± 8 years, 25 ± 4 kg m–2) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% V̇O2max) or resistance exercise (n = 10, 4 × 7 × 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced‐representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up‐regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated with rDNA gene dosage, as well as epigenetic changes in enhancer and non‐canonical MYC‐associated areas in rDNA, but not the promoter. A mouse model of in vivo metabolic RNA labelling and genetic myonuclear fluorescence labelling validated the effects of an acute hypertrophic stimulus on ribosome biogenesis and Myc transcription, and also corroborated rDNA enhancer and Myc‐associated methylation alterations specifically in myonuclei. The present study provides the first information on skeletal muscle genetic and rDNA gene‐wide epigenetic regulation of ribosome biogenesis in response to exercise, revealing novel roles for rDNA dosage and CpG methylation. Key points: Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery.A PCR‐based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE.Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non‐canonical MYC‐associated regions, but not the promoter.Myonuclear‐specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans.A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage. [ABSTRACT FROM AUTHOR]

Background: In the context of mass regulation, 'muscle memory' can be defined as long‐lasting cellular adaptations to hypertrophic exercise training that persist during detraining‐induced atrophy and may facilitate future adaptation. The cellular basis of muscle memory is not clearly defined but may be related to myonuclear number and/or epigenetic changes within muscle fibres. Methods: Utilizing progressive weighted wheel running (PoWeR), a novel murine exercise training model, we explored myonuclear dynamics and skeletal muscle miRNA levels with training and detraining utilizing immunohistochemistry, single fibre myonuclear analysis, and quantitative analysis of miRNAs. We also used a genetically inducible mouse model of fluorescent myonuclear labelling to study myonuclear adaptations early during exercise. Results: In the soleus, oxidative type 2a fibres were larger after 2 months of PoWeR (P = 0.02), but muscle fibre size and myonuclear number did not return to untrained levels after 6 months of detraining. Soleus type 1 fibres were not larger after PoWeR but had significantly more myonuclei, as well as central nuclei (P < 0.0001), the latter from satellite cell‐derived or resident myonuclei, appearing early during training and remaining with detraining. In the gastrocnemius muscle, oxidative type 2a fibres of the deep region were larger and contained more myonuclei after PoWeR (P < 0.003), both of which returned to untrained levels after detraining. In the gastrocnemius and plantaris, two muscles where myonuclear number was comparable with untrained levels after 6 months of detraining, myonuclei were significantly elongated with detraining (P < 0.0001). In the gastrocnemius, miR‐1 was lower with training and remained lower after detraining (P < 0.002). Conclusions: This study found that (i) myonuclei gained during hypertrophy are lost with detraining across muscles, even in oxidative fibres; (ii) complete reversal of muscle adaptations, including myonuclear number, to untrained levels occurs within 6 months in the plantaris and gastrocnemius; (iii) the murine soleus is resistant to detraining; (iv) myonuclear accretion occurs early with wheel running and can be uncoupled from muscle fibre hypertrophy; (v) resident (non‐satellite cell‐derived) myonuclei can adopt a central location; (vi) myonuclei change shape with training and detraining; and (vii) miR‐1 levels may reflect a memory of previous adaptation that facilitates future growth. [ABSTRACT FROM AUTHOR]

Disruption of circadian rhythms in humans and rodents has implicated a fundamental role for circadian rhythms in ageing and the development of many chronic diseases including diabetes, cardiovascular disease, depression and cancer. The molecular clock mechanism underlies circadian rhythms and is defined by a transcription–translation feedback loop with Bmal1 encoding a core molecular clock transcription factor. Germline Bmal1 knockout (Bmal1 KO) mice have a shortened lifespan, show features of advanced ageing and exhibit significant weakness with decreased maximum specific tension at the whole muscle and single fibre levels. We tested the role of the molecular clock in adult skeletal muscle by generating mice that allow for the inducible skeletal muscle-specific deletion of Bmal1 (iMSBmal1). Here we show that disruption of the molecular clock, specifically in adult skeletal muscle, is associated with a muscle phenotype including reductions in specific tension, increased oxidative fibre type, and increased muscle fibrosis similar to that seen in the Bmal1 KO mouse. Remarkably, the phenotype observed in the iMSBmal1−/− mice was not limited to changes in muscle. Similar to the germline Bmal1 KO mice, we observed significant bone and cartilage changes throughout the body suggesting a role for the skeletal muscle molecular clock in both the skeletal muscle niche and the systemic milieu. This emerging area of circadian rhythms and the molecular clock in skeletal muscle holds the potential to provide significant insight into intrinsic mechanisms of the maintenance of muscle quality and function as well as identifying a novel crosstalk between skeletal muscle, cartilage and bone. [ABSTRACT FROM AUTHOR]

Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt2. However, it remains unknown whether exercise training stimulates vessel growth in human adipose tissue, and it remains unknown whether adipose angiogenesis is mediated by angiopoietin signaling. We sought to determine whether insulin-resistant subjects would display an impaired angiogenic response to aerobic exercise training. Insulin-sensitive ( IS, N = 12) and insulin-resistant ( IR, N = 14) subjects had subcutaneous adipose and muscle ( vastus lateralis) biopsies before and after 12 weeks of cycle ergometer training. In both tissues, we measured vessels and expression of pro-angiogenic genes. Exercise training did not increase insulin sensitivity in IR Subjects. In skeletal muscle, training resulted in increased vessels/muscle fiber and increased Angpt2:Angpt1 ratio in both IR and IS subjects. However, in adipose, exercise training only induced angiogenesis in IS subjects, likely due to chronic suppression of VEGFA expression in IR subjects. These results indicate that skeletal muscle of IR subjects exhibits a normal angiogenic response to exercise training. However, the same training regimen is insufficient to induce angiogenesis in adipose tissue of IR subjects, which may help to explain why we did not observe improved insulin sensitivity following aerobic training. [ABSTRACT FROM AUTHOR]

Objective To identify muscle physiologic properties that may contribute to postexertional fatigue and malaise in women with fibromyalgia (FM). Methods Healthy postmenopausal women with (n = 11) and without (n = 11) FM, ages 51-70 years, participated in this study. Physical characteristics and responses to self-reported questionnaires were evaluated. Strength loss and tissue oxygenation in response to a fatiguing exercise protocol were used to quantify fatigability and the local muscle hemodynamic profile. Muscle biopsies were performed to assess between-group differences in baseline muscle properties using histochemical, immunohistochemical, and electron microscopic analyses. Results There was no significant difference between healthy controls and FM patients in muscle fatigue in response to exercise. However, self-reported fatigue and pain were correlated with prolonged loss of strength following 12 minutes of recovery in patients with FM. Although there was no difference in percent succinate dehydrogenase (SDH)-positive (type I) and SDH-negative (type II) fibers or in mean fiber cross-sectional area between groups, FM patients exhibited greater variability in fiber size and altered fiber size distribution. In healthy controls only, fatigue resistance was strongly correlated with the size of SDH-positive fibers and hemoglobin oxygenation. In contrast, FM patients with the highest percentage of SDH-positive fibers recovered strength most effectively, and this was correlated with capillary density. However, overall, capillary density was lower in the FM group. Conclusion Peripheral mechanisms, i.e., altered muscle fiber size distribution and decreased capillary density, may contribute to postexertional fatigue in FM. Understanding of these defects in fibromyalgic muscle may provide valuable insight with regard to treatment. [ABSTRACT FROM AUTHOR]

Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would augment the muscle response to PRT in healthy women and men aged 65 and older. In a randomized, double‐blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT. Although responses to PRT varied, placebo gained more lean body mass (p = .003) and thigh muscle mass (p < .001) than metformin. CT scan showed that increases in thigh muscle area (p = .005) and density (p = .020) were greater in placebo versus metformin. There was a trend for blunted strength gains in metformin that did not reach statistical significance. Analyses of vastus lateralis muscle biopsies showed that metformin did not affect fiber hypertrophy, or increases in satellite cell or macrophage abundance with PRT. However, placebo had decreased type I fiber percentage while metformin did not (p = .007). Metformin led to an increase in AMPK signaling, and a trend for blunted increases in mTORC1 signaling in response to PRT. These results underscore the benefits of PRT in older adults, but metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals. ClinicalTrials.gov Identifier: NCT02308228. [ABSTRACT FROM AUTHOR]