Skeletal muscle health and function are guaranteed by a finely tuned balance between synthesis of new proteins and degradation of damaged structures and organelles. However, under catabolic conditions degradative processes exceed de novo protein synthesis and organelle biogenesis leading to muscle atrophy, which is regulated by a specific genetically-encoded program.
In the search for new players involved in muscle mass regulation, in the past years we identified Fbxo30/MUSA1, a previously uncharacterized E3 ubiquitin ligase that sits at the crossroads of two fundamental pathways controlling muscle mass; indeed, MUSA1 expression is driven by FoxO3 during catabolic conditions, while it is suppressed by the BMP signaling.
To better characterize MUSA1 role in skeletal muscle physiology, we generated muscle-specific knock-out mice. MUSA1 deletion leads to progressive sarcomere disorganization in knock-out muscles. In particular, histological and electron microscope analyses revealed the presence of wide areas within aged knock-out muscle fibers characterized by the presence of indigested proteinaceous material completely disrupting sarcomeres architecture. Moreover, these aggregates appear as enlarged Z-line, resembling nemaline rods, a feature typical of nemaline myopathies. As a consequence, these ultrastructural alterations lead to muscle weakness in aged knock-out animals. In line with these evidences, aged knock-out muscles proteomes show progressive accumulation of proteins important for sarcomeres and cytoskeleton assembly and stabilization, together with Z-line components. For this reason, we speculate that MUSA1 could be involved in some of these proteins turnover. Indeed, we demonstrated by in vitro ubiquitination assay that MUSA1 is responsible for actinin 3 (ACTN3) poly-ubiquitination when coupled with the E2 conjugating enzyme UbcH2.
Concluding, our data support MUSA1 as a novel critical player in controlling Z-line homeostasis together with muscle function. However, further investigations are needed to better characterize MUSA1 substrates and to precisely dissect the molecular pathogenic mechanisms involved in the perspective of therapeutic intervention.