SUMOylation is a post-translational modification regulating skeletal muscle pathophysiology

Abstract

The research of this thesis is focused to investigate the role of SUMOylation, a protein post-translational modification reaction, implemented to the skeletal muscle pathophysiology area. SUMOylation is regulated by an enzymatic cascade of coordinated events capable of the reversible attachment of the Small Ubiquitin-like Modifier (SUMO) on to the targeted proteins. This reaction is highly susceptible to intra- or extracellular stimuli and responds immediately by altering the expression of its enzymes and the final SUMOylated products as an adaptation to the new status.

Skeletal muscle is a complex organ and it is unfortunately affected by severe diseases, which represent widespread pathologies affecting millions of people every year. Until now, despite many studies performed on the field, there is still a lack of information about the cellular and molecular mechanisms predicting or describing the early events of human muscle pathologies. We investigated different processes occurring among the SUMO network and the skeletal muscle functions and related them to the normal muscle activities or muscle alterations, from rodent models of muscle pathologies to human muscle biopsies. We described a tight correlation between the abundance of SUMO conjugated proteins and the different skeletal muscle fiber types. This association was quickly altered as a consequence of muscle activity changes or early events in acquired muscular disorders. We provided also a new skeletal muscle embryological classification based exclusively on the diverse abundances and distribution of the SUMO enzymes.

A combination of innovative techniques allowed us to identify and validate new SUMO skeletal muscle targets and determine the modulation of the SUMO enzymes abundances during myogenesis and the progression of acquired muscle diseases. These results assigned to some SUMO components a potential biomarker function to predict skeletal muscle dysfunctions. Thus, the investigation on skeletal muscle disuse allowed us to discover a new transcriptional regulation mechanism of the E2 SUMO enzyme, Ubc9, mediated by the transcriptor factor PAX6 in soleus muscles under unloaded conditions. Finally, we proved that targeting the SUMO pathway using chemical drugs as BGP-15 or anacardic acid have a positive effect on the treatment of myopathies and improving myogenesis under hyperglycemic conditions.