Requirement of myomaker-mediated stem cell fusion for skeletal muscle hypertrophy

Abstract

Fusion of skeletal muscle stem/progenitor cells is required for proper development and regeneration, however the significance of this process during adult muscle hypertrophy has not been explored. In response to muscle overload after synergist ablation in mice, we show that myomaker, a muscle specific membrane protein essential for myoblast fusion, is activated mainly in muscle progenitors and not myofibers. We rendered muscle progenitors fusion-incompetent through genetic deletion of myomaker in muscle stem cells and observed a complete reduction of overload-induced hypertrophy. This blunted hypertrophic response was associated with a reduction in Akt and p70s6k signaling and protein synthesis, suggesting a link between myonuclear accretion and activation of pro-hypertrophic pathways. Furthermore, fusion-incompetent muscle exhibited increased fibrosis after muscle overload, indicating a protective role for normal stem cell activity in reducing myofiber strain associated with hypertrophy. These findings reveal an essential contribution of myomaker-mediated stem cell fusion during physiological adult muscle hypertrophy.DOI: http://dx.doi.org/10.7554/eLife.20007.001

Specific labelling of myonuclei by an antibody against pericentriolar material 1 on skeletal muscle tissue sections

“…This model is to a large extent based on histology with classical chemical staining methods and has recently been challenged by direct observation of myonuclei by in vivo imaging (reviewed in 10,12 ). The new results indicate that recruitment of myonuclei precedes cell enlargement 7 and is obligatory at least for major de novo hypertrophy, 9,13,14 and in direct conflict with the old model, myonuclei are not lost during atrophy. 6,11 The "extra" nuclei that have been acquired by previous hypertrophy seem to be permanent and are aiding in a more rapid subsequent regrowth.…”

Pericyte transplantation improves skeletal muscle recovery following hindlimb immobilization

“…Muscle-resident stem/stromal cells demonstrate significant potential to repair skeletal muscle following injury. The role for the SC Pax7 + in repair of skeletal muscle injury is well acknowledged (15,16), but the extent to which these cells influence growth in response to loading remains controversial (17)(18)(19)(20)(21). SCs may not fuse or provide nuclear support for protein synthesis in adult muscle as previously proposed, but they may fine-tune the growth ABBREVIATIONS: APC, allophycoctanin; Ang, angiogenin; Atf4, activating transcription factor 4; CBC, Roy J.…”

Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity

“…These MRFs trigger the expression of later myogenic transcription factors (such as myogenin and myocyte enhancer factor 2) (12,13) and subsequently that of muscle-specific structural genes (troponins and myosin heavy chains) (14,15) and genes involved in myoblast fusion (caveolin-3, myomixer, and myomaker) (16)(17)(18)(19)(20). Recently, myomaker (20) together with myomixer (17), also named myomerger (18) or minion (19), have been demonstrated to act as the crucial molecular pair necessary and sufficient for the activation of cytoskeletal remodeling, membrane rearrangement, and coalescence required for myoblast fusion (17)(18)(19)(20)(21)(22)(23).…”