Muscle memory: myonuclear accretion, maintenance, morphology, and miRNA levels with training and detraining in adult mice

Abstract

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.

Genetic and Epigenetic Regulation of Skeletal Muscle Ribosome Biogenesis with Exercise

“…Acute RE also promotes a reorganization of rDNA methylation patterns along the repeat. The specific consequences and lasting effects of this acute epigenetic remodeling of rDNA deserve further investigation, but if persistent over time, could contribute to a previously observed epigenetic "epi-memory" of prior exercise exposure that facilitates future muscle adaptability (Sharples et al, 2016;Seaborne et al, 2018;Moberg et al, 2020;Murach et al, 2020;Snijders et al, 2020).…”

“…With these parallel approaches, we reveal novel information on genetic and epigenetic transcriptional control of the translational apparatus following exercise. Our findings may have implications for individual heterogeneity in exercise responsiveness to training (Ahtiainen et al, 2016;Sparks, 2017;Lavin et al, 2019), as well as the epigenetic mechanisms of potentiated exercise adaptability related to long-term cellular "muscle memory" (Murach et al, 2019;Murach et al, 2020;Snijders et al, 2020).…”

Molecular Regulation of Skeletal Muscle Growth and Organelle Biosynthesis: Practical Recommendations for Exercise Training

“…As suggested by authors [ 237 ], the muscle memory of hypertrophic response may be independent of myonuclear number, and probably due to myonuclear DNA methylation, histone modifications, miRNA expression, and other epigenetic mechanisms. As underlined in the study of Murach et al [ 48 ], miR-1 downregulation after a resistance training program remains lower after six months of detraining and could contribute to make a kind of memory induced by a first training adaptation to facilitate regrowth during further exposure. Reinforcing the role of miRNAs in skeletal muscle mass maintenance, it was suggested that miR-21 expression in SCs and muscle could inhibit myogenesis in old mice and contribute to the decline in muscle regeneration during aging [ 238 ].…”

“…Importantly, the involvement of satellite cells in skeletal muscle mass regulation has been recently questioned but new data highlighted their importance in myonuclear accretion and muscle remodeling during exercise training [ 48 , 49 , 50 ]. Finally, recent data underlined the importance of an epigenetic regulation (e.g., DNA and histone modifications, expression of specific microRNAs) of skeletal muscle mass, especially during resistance exercise [ 51 , 52 ].…”

The Effects of Gender Affirming Treatment on the Sporting Performance and Muscle Memory of Transgender Athletes. A Protocol for The Tavistock Transgender Athlete Study.

“…Transwomen, who have been exposed to higher circulating levels of testosterone during puberty than cisgender women, may have higher myonuclei per fibre values that are then retained for prolonged periods after the commencement of GAT (despite decrements in muscle mass) giving them a retained advantage that may be permanent [31]. Myonuclear permanence may also not be the predominant mechanism in the muscle memory phenomenon and that other mechanisms such as an epigenetic memory or residual miRNA levels may play a significant role [32,33].…”