Myonuclei gained during exercise-induced skeletal muscle hypertrophy may be long-lasting and could facilitate future muscle adaptability after deconditioning, a concept colloquially termed “muscle memory.” The evidence for this is limited, mostly due to the lack of a murine exercise-training paradigm that is nonsurgical and reversible. To address this limitation, we developed a novel progressive weighted-wheel-running (PoWeR) model of murine exercise training to test whether myonuclei gained during exercise persist after detraining. We hypothesized that myonuclei acquired during training-induced hypertrophy would remain following loss of muscle mass with detraining. Singly housed female C57BL/6J mice performed 8 wk of PoWeR, while another group performed 8 wk of PoWeR followed by 12 wk of detraining. Age-matched sedentary cage-dwelling mice served as untrained controls. Eight weeks of PoWeR yielded significant plantaris muscle fiber hypertrophy, a shift to a more oxidative phenotype, and greater myonuclear density than untrained mice. After 12 wk of detraining, the plantaris muscle returned to an untrained phenotype with fewer myonuclei. A finding of fewer myonuclei simultaneously with plantaris deconditioning argues against a muscle memory mechanism mediated by elevated myonuclear density in primarily fast-twitch muscle. PoWeR is a novel, practical, and easy-to-deploy approach for eliciting robust hypertrophy in mice, and our findings can inform future research on the mechanisms underlying skeletal muscle adaptive potential and muscle memory.
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.
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 ¼ 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.
Although aberrant mTORC1 signaling has been well established in models of obesity, little is known about its repressor, REDD1. Therefore, the initial goal of this study was to determine the role of REDD1 on mTORC1 in obese skeletal muscle. REDD1 expression (protein and message) and mTORC1 signaling (S6K1, 4E-BP1, raptor-mTOR association, Rheb GTP) were examined in lean vs. ob/ob and REDD1 wild-type (WT) vs. knockout (KO) mice, under conditions of altered nutrient intake [fasted and fed or diet-induced obesity (10% vs. 60% fat diet)]. Despite higher (P < 0.05) S6K1 and 4E-BP1 phosphorylation, two models of obesity (ob/ob and diet-induced) displayed elevated (P < 0.05) skeletal muscle REDD1 expression compared with lean or low-fat-fed mouse muscle under fasted conditions. The ob/ob mice displayed elevated REDD1 expression (P < 0.05) that coincided with aberrant mTORC1 signaling (hyperactive S6K1, low raptor-mTOR binding, elevated Rheb GTP; P < 0.05) under fasted conditions, compared with the lean, which persisted in a dysregulated fashion under fed conditions. REDD1 KO mice gained limited body mass on a high-fat diet, although S6K1 and 4E-BP1 phosphorylation remained elevated (P < 0.05) in both the low-fat and high-fat-fed KO vs. WT mice. Similarly, the REDD1 KO mouse muscle displayed blunted mTORC1 signaling responses (S6K1 and 4E-BP1, raptor-mTOR binding) and circulating insulin under fed conditions vs. the robust responses (P < 0.05) in the WT fed mouse muscle. These studies suggest that REDD1 in skeletal muscle may serve to limit hyperactive mTORC1, which promotes aberrant mTORC1 signaling responses during altered nutrient states.
To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a nontranslational stimulus and/or have been performed over a relatively short time frame. Although it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long-term physical activity. The current study was designed to determine whether reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-diphtheria toxin A (DTA) mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 mo. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume, and the size of muscle proprioceptors (spindle fibers). Furthermore, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of G protein-coupled receptor (GPCR) signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long-term physical activity. These findings suggest that satellite cells play a role in preserving physical function during aging and influence muscle adaptation during sustained periods of physical activity.
Satellite cells are required for post-natal development, skeletal muscle regeneration across the lifespan and skeletal muscle hypertrophy prior to maturity. Our group has aimed to address whether satellite cells are required for hypertrophic growth in mature skeletal muscle. Here, we generated a comprehensive characterization and transcriptome-wide profiling of skeletal muscle during adaptation to exercise in the presence or absence of satellite cells in order to identify distinct phenotypes and gene networks influenced by satellite cell content. We administered vehicle or tamoxifen to adult Pax7-DTA mice and subjected them to progressive weighted wheel running (PoWeR). We then performed immunohistochemical analysis and whole-muscle RNA-seq of vehicle (SC+) and tamoxifen-treated (SC-) mice. Further, we performed single myonuclear RNA-seq to provide detailed information on how satellite cell fusion affects myonuclear transcription. We show that while skeletal muscle can mount a robust hypertrophic response to PoWeR in the absence of satellite cells, growth and adaptation are ultimately blunted. Transcriptional profiling reveals several gene networks key to muscle adaptation are altered in the absence of satellite cells.
Using a mouse model of conditional and inducible in vivo fluorescent myonuclear labeling (HSA-GFP), sorting purification of nuclei, low-input reduced representation bisulfite sequencing (RRBS), and a translatable and reversible model of exercise (progressive weighted wheel running, PoWeR), we provide the first nucleus type-specific epigenetic information on skeletal muscle adaptation and detraining. Adult (>4 month) HSA-GFP mice performed PoWeR for 8 weeks then detrained for 12 weeks; age-matched untrained mice were used to control for the long duration of the study. Myonuclei and interstitial nuclei from plantaris muscles were isolated for RRBS. Relative to untrained, PoWeR caused similar myonuclear CpG hypo- and hypermethylation of promoter regions and substantial hypomethylation in interstitial nuclear promoters. Over-representation analysis of promoters revealed a larger number of hyper- versus hypomethylated pathways in both nuclear populations after training and evidence for reciprocal regulation of methylation between nucleus types, with hypomethylation of promoter regions in Wnt signaling-related genes in myonuclei and hypermethylation in interstitial nuclei. After 12 weeks of detraining, promoter CpGs in documented muscle remodeling-associated genes and pathways that were differentially methylated immediately after PoWeR were persistently differentially methylated in myonuclei, along with long-term promoter hypomethylation in interstitial nuclei. No enduring gene expression changes in muscle tissue were observed using RNA-sequencing. Upon 4 weeks of retraining, mice that trained previously grew more at the whole muscle and fiber type-specific cellular level than training naïve mice, with no difference in myonuclear number. Muscle nuclei have a methylation epi-memory of prior training that may augment muscle adaptability to retraining.
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