Nuclear actin and Mrtfs control disuse muscle atrophy via Srf activity regulation Running title: The actin/Mrtfs/Srf axis controls disuse atrophy

Skeletal muscle atrophy is a debilitating process associated with a wide variety of conditions including inactivity, disease and aging. Here, we demonstrate that the actin/Mrtfs/Srf pathway is specifically downregulated in muscle atrophy induced by disuse in mice. We show in vivo that the abolition of mechanical signals leads to rapid accumulation of G-actin in myonuclei and export of the Srf coactivator Mrtf-A, resulting in Mrtfs/Srf-dependent transcription decrease that contributes to atrophy. We demonstrate that inhibition of the actin/Mrtfs/Srf axis by overexpression of nuclear non-polymerizable actin, pharmacological inhibition of Mrtfs/Srf and muscle-specific Srf deletion worsens denervation-induced atrophy. Conversely, maintenance of high Srf or Mrtfs activity 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/Mrtfs/Srf pathway, highlighting Srf as a key mediator of mechanotransduction in muscle. Jo ur na l o f C el l S ci en ce A cc ep te d m an us cr ip t