AUTHOR=Joanne Pierre , Hovhannisyan Yeranuhi , Bencze Maximilien , Daher Marie-Thérèse , Parlakian Ara , Toutirais Geraldine , Gao-Li Jacqueline , Lilienbaum Alain , Li Zhenlin , Kordeli Ekaterini , Ferry Arnaud , Agbulut Onnik 

TITLE=Absence of Desmin Results in Impaired Adaptive Response to Mechanical Overloading of Skeletal Muscle

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.662133

DOI=10.3389/fcell.2021.662133

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> Desmin is a muscle-specific protein belonging to the intermediate filament family. Desmin mutations are linked to skeletal muscle defects, including inherited myopathies with severe clinical manifestations. The aim of this study was to examine the role of desmin in skeletal muscle remodeling and performance gain induced by muscle mechanical overloading which mimics resistance training.</p><p><bold>Methods:</bold> Plantaris muscles were overloaded by surgical ablation of gastrocnemius and soleus muscles. The functional response of plantaris muscle to mechanical overloading in desmin-deficient mice (<italic>Des</italic>KO, <italic>n</italic> = 32) was compared to that of control mice (<italic>n</italic> = 36) after 7-days or 1-month overloading. To elucidate the molecular mechanisms implicated in the observed partial adaptive response of <italic>Des</italic>KO muscle, we examined the expression levels of genes involved in muscle growth, myogenesis, inflammation and oxidative energetic metabolism. Moreover, ultrastructure and the proteolysis pathway were explored.</p><p><bold>Results:</bold> Contrary to control, absolute maximal force did not increase in <italic>Des</italic>KO muscle following 1-month mechanical overloading. Fatigue resistance was also less increased in <italic>Des</italic>KO as compared to control muscle. Despite impaired functional adaptive response of <italic>Des</italic>KO mice to mechanical overloading, muscle weight and the number of oxidative MHC2a-positive fibers per cross-section similarly increased in both genotypes after 1-month overloading. However, mechanical overloading-elicited remodeling failed to activate a normal myogenic program after 7-days overloading, resulting in proportionally reduced activation and differentiation of muscle stem cells. Ultrastructural analysis of the plantaris muscle after 1-month overloading revealed muscle fiber damage in <italic>Des</italic>KO, as indicated by the loss of sarcomere integrity and mitochondrial abnormalities. Moreover, the observed accumulation of autophagosomes and lysosomes in <italic>Des</italic>KO muscle fibers could indicate a blockage of autophagy. To address this issue, two main proteolysis pathways, the ubiquitin-proteasome system and autophagy, were explored in <italic>Des</italic>KO and control muscle. Our results suggested an alteration of proteolysis pathways in <italic>Des</italic>KO muscle in response to mechanical overloading.</p><p><bold>Conclusion:</bold> Taken together, our results show that mechanical overloading increases the negative impact of the lack of desmin on myofibril organization and mitochondria. Furthermore, our results suggest that under these conditions, the repairing activity of autophagy is disturbed. Consequently, force generation is not improved despite muscle growth, suggesting that desmin is required for a complete response to resistance training in skeletal muscle.</p>