## 4 Implication of Satellite Cells and Myonuclear Accretion
However, these results were recently debated by [PERSON] and coworkers who found a large overload-induced hypertrophy, which was prevented in satellite cell-deficient mice under the same experimental conditions [201]. In accordance with these findings, other methodological approaches based on SCs inhibition by _s_-irradiation indicated that muscle hypertrophy was prevented when SCs recruitment was blunted [199]. The conditional depletion of more than 90% of SCs of transgenic Pax7-DTA mice yielded also blunted hypertrophic and myonuclear accretion responses [226]. By using young mice genetically deleted of fusion-required serum response factor, [PERSON] confirmed the essential role of SCs for overload-induced hypertrophy [227]. In the same way, CDK1 deletion impaired SCs proliferation and showed strong limitation of overload-induced hypertrophy [228]. In a study from [PERSON] et al., authors abrogated fusion of muscle progenitors by specifically deleting myomaker (i.e., a membrane protein involved in myoblast fusion). Results revealed that myonuclear accrual and hypertrophic response were blunted following synergistic ablation [229]. Importantly, another study from [PERSON] and coworkers addressed the question if myonuclei accrual is required in a physiological setting that did not use supra-physiological models. Authors submitted mice to high-intensity interval training (HIIT) during eight weeks and demonstrated that abrogation of muscle progenitor cells fusion at the onset of the protocol blocked myonuclear accretion and hypertrophic response [187]. In addition, muscle fibrosis was observed, as well as exercise intolerance in myomaker-deficient mice. To distinguish differential requirement of muscle progenitor cells fusion between early and late stages, the authors also abrogated muscle progenitor cells fusion after four weeks of training. Results showed attenuated hypertrophy although mice no longer presented exercise intolerance or fibrosis. Authors suggested that myonuclear accretion promotes muscle repair in the early stage of the training protocol and muscle growth during the last stage. Finally, maturational ages are of importance in the involvement of SCs and myonuclear accretion during postnatal growth. Indeed, it was suggested that in response to overload, muscle fiber hypertrophy was prevented in young SCs depleted mice, but not in adult mice (>four months old) [230]. It was also shown that SCs deletion reduced myonuclear number, prepubertal myofiber hypertrophic growth, and force generation [231]. According to these findings, there is evidence that SCs fusion plays an active role in post-natal muscle hypertrophy that can be dependent on factors as age. However, as hypertrophy was not totally blunted when SCs were impaired in some studies [226; 232], fusion-independent mechanisms may also have a role within the muscle tissue to ensure partial hypertrophy. The canonical function of SCs during hypertrophic response of adult myofibers is myonuclear accretion via cells fusion. Nevertheless, [PERSON] et al. underlined that SCs also display fusion-independent roles through their secretory functions, showing that SCs communicate with muscle fibers without necessarily achieve fusion [233]. They previously demonstrated that SCs communicated with fibrogenic cells through exosomes to ensure correct regulation of the extracellular environment in response to hypertrophic stimuli [234]. This fusion-independent mechanism probably involves miRNAs that affect extracellular matrix [234]. Using a mice model of delayed SCs fusion, authors provided evidence that SCs also released extracellular vesicles to muscle fibers [233]. From their results, authors gave novel insights about SCs functions during hypertrophy. Thus, they suggest that coordination of the early hypertrophic response to overload may also be dependent of fusion-independent mechanisms (Figure 4).