Proteome dynamics reveal Leiomodin 1 as a key regulator of myogenic differentiation

During myogenic differentiation, the cellular architecture and proteome of muscle stem cells and myoblasts undergo extensive remodeling. These processes are partially understood and display alterations in disease and aging, resulting in impaired regeneration. Here, we used mass spectrometry to quantify the temporal dynamics of over 6000 proteins during myogenic differentiation. We identified the actin nucleator leiomodin 1 (LMOD1) among a restricted subset of cytoskeletal proteins increasing in abundance during early myogenic differentiation. LMOD1 is expressed by muscle stem cells in vivo and displays increased abundance during skeletal muscle regeneration in mice, particularly during early stages, suggesting its importance in myotube formation. Notably, LMOD1 knockdown in primary myoblasts and during regeneration severely affects differentiation, while its overexpression accelerates and improves myotube initiation. This suggests LMOD1 is a critical component regulating myogenic differentiation. Mechanistically, we show that LMOD1 physically and functionally interacts with the deacetylase sirtuin1 (SIRT1), a regulator of myogenic differentiation. We demonstrate that LMOD1 influences SIRT1 localization and the expression of its target genes. Consistently, depletion or pharmacological inhibition of SIRT1 partially rescues the differentiation impairment observed after LMOD1 knockdown. Our work identifies LMOD1 as a new regulator that might be targeted to improve muscle regeneration in aging and disease.