Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy

Abstract

<jats:title>Abstract</jats:title> <jats:p>The “canonical” function of Pax7+ muscle stem cells (satellite cells) during hypertrophic growth of adult muscle fibers is myonuclear donation via fusion to support increased transcriptional output. In recent years, however, emerging evidence suggests that satellite cells play an important secretory role in promoting load-mediated growth. Utilizing genetically modified mouse models of delayed satellite cell fusion and in vivo extracellular vesicle tracking, we provide evidence for satellite cell communication to muscle fibers during hypertrophy. Myogenic progenitor cell extracellular vesicle-mediated communication to myotubes in vitro influences extracellular matrix (ECM)-related gene expression, which is congruent with in vivo overload experiments involving satellite cell depletion, as well as in silico analyses. Satellite cell-derived extracellular vesicles can transfer a Cre-induced, cytoplasmic-localized fluorescent reporter to muscle cells as well as miRNAs that regulate ECM genes such as matrix metalloproteinase 9 (Mmp9), which may facilitate growth. Delayed satellite cell fusion did not limit long-term load-induced muscle hypertrophy indicating that early fusion-independent communication from satellite cells to muscle fibers is an under-appreciated aspect of satellite cell biology. We cannot exclude the possibility that satellite cell-mediated myonuclear accretion is necessary to maintain prolonged growth, specifically in the later phases of adaptation, but these data collectively highlight how extracellular vesicle delivery from satellite cells can directly contribute to mechanical load-induced muscle fiber hypertrophy, independent of cell fusion to the fiber.</jats:p>

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

“…<3 months in mice), 2,4 but that alternative epigenetic mechanisms such as myonuclear DNA methylation, histone modifications, or miRNA expression could explain muscle memory in the long‐term after myonuclear number has stabilized 12,70,73,74 ( Figure 9). Furthermore, myoblasts are shown to have a long‐term epigenetic memory of previous exposure to stress in vitro 75 , so satellite cells could theoretically contribute to muscle memory in myofibers via recently identified fusion‐independent mechanisms in vivo 76 . Future studies may employ newly developed voluntary 77 or involuntary resistance training paradigms (exercise dosage can be controlled for in the latter) 78,79 for mice that can complement PoWeR (recently reviewed here 31 ) and will aim to address how myonuclei are removed during detraining, the role of myonuclear translocation during exercise adaptation, whether epigenetic changes could explain myonuclear shape transformations with training and detraining, which exercise‐induced epigenetic alterations to myonuclei are permanent, and how miR‐1 could facilitate retraining adaptations.…”

Early satellite cell communication creates a permissive environment for long-term muscle growth

“…With mechanical loading-induced skeletal muscle hypertrophy, numerous lines of evidence across different species suggest that muscle fibers can adapt and grow appreciably without satellite cell fusion and myonuclear accretion (Murach et al, 2018a); however, long-term hypertrophy without satellite cells is attenuated concomitant with excess ECM accumulation (Fry et al, 2014a). Our laboratory recently showed that satellite cells may communicate with fibrogenic cells and muscle fibers (Murach et al, 2020c) via miRNA-containing extracellular vesicles (EVs) to regulate the muscle fiber milieu during hypertrophy. Presently, it is unclear whether early satellite cell-mediated secretory signaling throughout muscle is sufficient for long-term adult muscle hypertrophy or whether myonuclear addition is required to sustain hypertrophy.…”

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

“…The canonical function of SCs during hypertrophic response of adult myofibers is myonuclear accretion via cells fusion. Nevertheless, Murach 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.…”