Papel del péptido mitocondrial MOTS-c como agente miogénico

Abstract

Muscle system is essential for mobility, metabolism, and overall health. The formation of myotubes, a critical process in muscle development and regeneration, depends on a complex interaction of biochemical signals. Research in this field is fundamental for developing new therapies against degenerative muscle diseases such as sarcopenia (age-related muscle loss) and cachexia (muscle loss associated with chronic diseases). The discovery of mitochondrial peptides has opened new frontiers in understanding mitochondria-cell communication and its impact on various physiological functions. Among these peptides, MOTS-c has garnered attention due to its involvement in metabolic regulation and its potential impact on muscle health. MOTS-c is a 16-amino acid peptide encoded by the 12S rRNA gene of the mitochondrial genome. Previous studies have shown that MOTS-c plays an important role in energy homeostasis and the regulation of insulin sensitivity, but its influence on muscle biology is not yet fully understood. The aim of this doctoral thesis is to explore the role of MOTS-c in myotube formation and to understand the molecular mechanisms underlying its myogenic function, with particular attention to its interaction with the IL-6/JAK2/STAT3 signaling pathway. The central hypothesis is that MOTS-c can promote myotube formation and protect against muscle atrophy by inhibiting the activity of STAT3, a key protein in inflammatory and metabolic signaling. For the development of the experiments, molecular and cellular biology techniques such as cell transfection, myotube formation, luciferase assays, and evaluation of STAT3 activity through protein phosphorylation assays were used, employing murine and human cell models. The results of these experiments show that, through computational analysis, a possible SH2-binding site in MOTS-c was identified. The mutant version of the peptide at this site did not have the same myotube-promoting effect as the wildtype MOTS-c. On the other hand, it was observed that wild-type MOTS-c promotes myotube formation in both cell models, whereas the mutant version did not have the same effect. This finding suggests that the SH2-binding site is crucial for the myogenic function of MOTS-c. Additionally, wild-type MOTS-c, but not the mutant version, protected against the IL-6-induced reduction of myogenin, suggesting a specific interaction of MOTS-c with the IL-6/JAK2/STAT3 signaling pathway. Finally, it was discovered that MOTS-c, but not the mutant version, blocks the activity of the STAT3 protein, involved in IL-6 signaling. The inhibition of STAT3 by MOTS-c could be the mechanism by which it promotes myotube formation and protects against muscle atrophy. The results indicate that MOTS-c promotes myotube formation by inhibiting the transcriptional activity of STAT3, suggesting that its myogenic action is mediated by interference with IL-6/JAK2/STAT3 signaling. This makes MOTS-c a potential therapeutic target for treating muscle loss in conditions such as cachexia and sarcopenia. Therefore, it can be concluded that MOTS-c plays a significant role in promoting myotube formation and protecting against muscle atrophy through the inhibition of STAT3. This mitochondrial peptide represents a potential therapeutic agent for diseases involving muscle mass loss.