Leiomodin 1 promotes myogenic differentiation by modulating Sirtuin 1

During myogenic differentiation the architecture and proteome of muscle stem cells undergo extensive remodeling. These processes are only partially understood and display impairments in age and disease. Here, we used mass spectrometry to analyze proteome dynamics during myogenic differentiation. We identified the actin nucleator Leiomodin 1 (LMOD1) among a restricted set of proteins that increase in abundance during early phases of differentiation. LMOD1 is expressed by muscle stem cells in vivo and its levels increase with aging. Knockdown of LMOD1 in primary myoblasts severely affected myogenic differentiation and fusion of myotubes, while overexpression had the opposite effect. Mechanistically, we show that LMOD1 interacts with Sirtuin1 (SIRT1) and that both proteins follow similar changes in nuclear/cytoplasmic localization during differentiation. We demonstrate that LMOD1 influences SIRT1 localization and the expression of a subset of its target genes. Consistently, depletion or pharmacological inhibition of SIRT1 partially reverts the effects observed after LMOD1 knockdown. Our work identifies a novel regulator of myogenic differentiation that might be a potential target to improve muscle regeneration in aging and disease.