The role of SUMO pathway in pathophsiology of skeletal muscle

Skeletal muscles are highly evolved and essential organs comprising 40 % of the total human body weight. They are essential in maintaining posture, energy metabolism, secrete hormones and act as central reserves for amino acids. Despite many studies on muscle physiology, there is a lack of understanding in cellular and molecular mechanisms leading to muscle adaptation, regeneration and progression of muscular disorders.

Post-translational modifications (PTMs) markedly regulate the quality and the functionality of proteins in eukaryotic cells. One such PTM is the reversible conjugation of a 12 kDa moiety called Small Ubiquitin-like Modifier, SUMO, onto targeted proteins in a process termed SUMOylation. Alterations in expression or activity of SUMO conjugating/de-conjugating enzymes in association with genetic point mutations in the SUMO consensus sequence of specific targets have been implicated in conditions like cancer, diabetes, brain ischaemia, and cardiomyopathies. Given to the reversible and rapid dynamic response to detect alterations in physiological conditions, SUMO pathway is being extensively studied as a potential therapeutic target for some conditions of brain and cardiac muscle protection from diseases. Our interests are to translate the significance of the SUMO pathway to skeletal muscle health, investigate its modulation as consequence of adaptation to new muscle activities and study disturbances in the SUMO reaction that alter the SUMO conjugation on specific target proteins which are associated to skeletal muscle diseases.

Ventilator Induced Diaphragm Dysfunction (VIDD) is a condition characterized by muscle dysfunction that occurs as side effect of Mechanical Ventilation. In diaphragms isolated from rats exposed to Controlled Mechanical ventilated (CMV), we observed significant changes in the overall SUMO muscle proteins due to alteration in the abundance of SUMO enzymes transcripts resulting in determining a new subset of SUMO targets. We studied the beneficial use of the drug BGP-15 administrated during CMV treatment that recovered the muscle contractile function partially due to a reorganization of the SUMO reaction. We further identified and characterized some specific skeletal muscle proteins targeted by the SUMO, which are associated with particular muscle functions. Mainly, we focused the attention on the E3 muscle ubiquitin ligase, MuRF1. We described the specific SUMO target site, enzymes involved in the SUMO reaction and the consequence of this PTM related to the properties of this protein. This discovery will open new avenues to understand the multiple functions of MuRF1 in muscle physiology and contribute to better understanding of muscular disorders that result from deregulation of MuRF1 activities mediated by SUMO conjugation.

Finally, we provided an important facet to the differences in abundance of SUMO enzyme transcripts that we found across the different skeletal muscles to control their specific role along the body position. In conclusion, we also provided strong evidence of how the SUMO cycle may also be used as a cellular pathway target for new treatments for various skeletal muscle diseases.

List of scientific papers

I. A Proteomic Approach to Identify Alterations in the Small Ubiquitin-like Modifier (SUMO) Network during Controlled Mechanical Ventilation in Rat Diaphragm Muscle. Namuduri AV, Heras G, Mi J, Cacciani N, Hörnaeus K, Konzer A, Lind SB, Larsson L, Gastaldello S. Mol Cell Proteomics. 2017 June 16.
https://doi.org/10.1074/mcp.M116.066159

II. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction. Salah H, Li M, Cacciani N, Gastaldello S, Ogilvie H, Akkad H, Namuduri AV, Morbidoni V, Artemenko KA, Balogh G, Martinez-Redondo V, Jannig P, Hedström Y, Dworkin B, Bergquist J, Ruas J, Vigh L, Salviati L, Larsson L. Sci Transl Med. 2016 Aug 3.
https://doi.org/10.1126/scitranslmed.aaf7099

III. Muscle RING-finger protein-1 (MuRF1) functions and cellular localization are regulated by SUMO1 post-translational modification. Heras G, Namuduri AV, Traini L, Shevchenko G, Falk A, Bergström Lind S, Mi J, Tian G, Gastaldello S. J Mol Cell Biol. 2018 June 4.
https://doi.org/10.1093/jmcb/mjy036

IV. The abundance of SUMO enzymes is fiber type dependent among skeletal muscles and it is altered in early event of muscle disuse. Namuduri AV, Heras G, Lauschke MV, Vitadello M, Traini L, Gorza L, Gastaldello S. [Manuscript]