Primary cilia in satellite cells are the mechanical sensors for muscle hypertrophy

Abstract

Skeletal muscle atrophy is commonly associated with aging, immobilization, muscle unloading, and congenital myopathies. Generation of mature muscle cells from skeletal muscle satellite cells (SCs) is pivotal in repairing muscle tissue. Exercise therapy promotes muscle hypertrophy and strength. Primary cilium is implicated as the mechanical sensor in some mammalian cells, but its role in skeletal muscle cells remains vague. To determine mechanical sensors for exercise-induced muscle hypertrophy, we established three SC-specific cilium dysfunctional mouse models-<i>Myogenic factor 5</i> (<i>Myf5</i>)<i>-Arf-like Protein 3</i> (<i>Arl3</i>)<i>^-/-, Paired box protein Pax-7</i> (<i>Pax7</i>)-<i>Intraflagellar transport protein 88 homolog</i> (<i>Ift88</i>)<i>^-/-</i>, and <i>Pax7-Arl3^-/-</i>-by specifically deleting a ciliary protein ARL3 in MYF5-expressing SCs, or IFT88 in PAX7-expressing SCs, or ARL3 in PAX7-expressing SCs, respectively. We show that the <i>Myf5-Arl3^-/-</i> mice develop grossly the same as WT mice. Intriguingly, mechanical stimulation-induced muscle hypertrophy or myoblast differentiation is abrogated in <i>Myf5-Arl3^-/-</i> and <i>Pax7-Arl3^-/-</i> mice or primary isolated <i>Myf5-Arl3^-/-</i> and <i>Pax7-Ift88^-/-</i> myoblasts, likely due to defective cilia-mediated Hedgehog (Hh) signaling. Collectively, we demonstrate SC cilia serve as mechanical sensors and promote exercise-induced muscle hypertrophy via Hh signaling pathway.