Elevated myonuclear density during skeletal muscle hypertrophy in response to training is reversed during detraining

Abstract

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.

Muscle atrophy and regeneration associated with behavioural loss and recovery of function after sciatic nerve crush

“…Consistent with the decrease in fibre CSA following denervation, the ratio fibre CSA per nuclear profile was 12%‐14% smaller at both 10 and 30 dpc (Figure C) . These results are consistent with recent reports evidencing that both fibre atrophy caused by denervation, nerve impulse bloc (see also below) or unloading, and fibre growth caused by loading or re‐training can occur without significant net change of myonuclei density see however also …”

“…72,73 These results are consistent with recent reports evidencing that both fibre atrophy caused by denervation, nerve impulse bloc (see also below) or unloading, and fibre growth caused by loading or re-training can occur without significant net change of myonuclei density 74,75 see however also. 39,[76][77][78] In this study, we also recorded an increased occurrence of myonuclei with a central position, a change that became significant at 30 dpc ( Figures 3D and 4A). Such nuclei are believed to be newly incorporated into the fibre and to derive from the SC niche (see Introduction) suggesting an accretion of myonuclei during the re-growth of the fibres once they became re-innervated (10-14 dpc) which matches the concurrent increase in MDF and NumbL mRNAs (see below).…”

“…However, we cannot provide evidence for the origin of these central nuclei since our experimental design did not include tissue labelling of markers for SCs or differentiating myoblasts, still our data would be consistent with a small flux of myonuclei through the sequential atrophy and re-growth processes following nerve crush. This issue certainly deserves further attention (see also below) especially in the light of recent observations evidencing that genetic reduction/ablation of the SC pool in adult (>4-month-old) mice does not prevent myofibre growth in response to loading or myofibre re-growth following atrophy in adult animals (>4 month old) 79-81 see however 39,76 ; reviewed in. 38,82 Complementary to the nerve crush model used here is chronic denervation where re-innervation is prevented 74,83,84 and tertrotoxin blockage of axon impulses (TTX; 74,[83][84][85][86][87] ).…”

Exercise promotes satellite cell contribution to myofibers in a load-dependent manner

“…Satellite cells (SCs) are a unique population of stem cells that remain quiescent for the majority of time, but upon activation can proliferate asymmetrically and fuse with myofibers (Tierney and Sacco, 2016). It has been hypothesized that SCs play a supportive role in muscular remodeling by exercise, because SC accumulation as well as myonuclear accretion have been observed during episodes of hypertrophy (Dungan et al, 2019;Fry et al, 2014;Goh et al, 2019;Goh and Millay, 2017). Yet, the quantitative extent of SC contribution to myonuclei was not demonstrated by these studies.…”

Transcriptional memory in skeletal muscle. Don't forget (to) exercise

“…Similarly, a recent human study found no increase in myonuclear number that would accompany gains in muscle force and mass in the course of 10 weeks of leg strength training (Psilander et al, 2019). Further complication arises from a recent murine study that reported training‐induced increases in myonuclear density but found no evidence for a retention of these newly recruited myonuclei that would last over a subsequent period of detraining (Dungan et al, 2019). Therefore it does not surprise that the question as to the overall contribution of SC fusion in resistance exercise adaptation is a matter of ongoing debate (Gundersen, 2016; Murach et al, 2018).…”