Nuclear actin and myocardin-related transcription factors control disuse muscle atrophy through regulation of Srf activity

Skeletal muscle atrophy is a debilitating process that is associated with a wide variety of conditions including inactivity, disease and aging. Here, we demonstrate that the actin, myocardin-related transcription factors and serum response factor (actin-Mrtf-Srf) pathway is specifically downregulated in the muscle atrophy that is induced through disuse in mice. We show in vivo that the abolition of mechanical signals leads to the rapid accumulation of G-actin in myonuclei and the export of the Srf coactivator Mrtf-A, resulting in a decrease of Mrtf-Srf-dependent transcription that contributes to atrophy. We demonstrate that inhibition of the actin-Mrtf-Srf axis through overexpression of nuclear non-polymerizable actin, through pharmacological inhibition of Mrtf-Srf and through muscle-specific Srf deletion worsens denervation-induced atrophy. Conversely, maintenance of high levels of activity of Srf or Mrtfs in denervated muscle, through overexpression of constitutively active derivatives, counteracts atrophy. Altogether, our data provide new mechanistic insights into the control of muscle mass upon disuse atrophy by the actin-Mrtf-Srf pathway, highlighting Srf as a key mediator of mechanotransduction in muscle.