Abstract
Depletion of skeletal muscle protein mainly results from enhanced protein breakdown, caused by activation of proteolytic systems such as the Ca2+-dependent and the ATP-ubiquitin-dependent ones. In the last few years, enhanced expression and bioactivity of myostatin have been reported in several pathologies characterized by marked skeletal muscle depletion. More recently, high myostatin levels have been associated with glucocorticoid-induced hypercatabolism. The search for therapeutical strategies aimed at preventing/correcting protein hypercatabolism has been directed to inhibit humoral mediators known for their pro-catabolic action, such as TNFα. The present study has been aimed to investigate the involvement of TNFα in the regulation of both myostatin expression and intracellular protein catabolism, and the possibility to interfere with such modulations by means of amino acid supplementation. For this purpose, C2C12 myotubes exposed to TNFα in the presence or in the absence of amino acid (glutamine or leucine) supplementation have been used. Myotube treatment with TNFα leads to both hyperexpression of the muscle-specific ubiquitin ligase atrogin-1, and enhanced activity of the Ca2+-dependent proteolytic system. These changes are associated with increased myostatin expression. Glutamine supplementation effectively prevents TNFα-induced muscle protein loss and restores normal myostatin levels. The results shown in the present study indicate a direct involvement of TNFα in the onset of myotube protein loss and in the perturbation of myostatin-dependent signaling. In addition, the protective effect exerted by glutamine suggests that amino acid supplementation could represent a possible strategy to improve muscle mass.
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Acknowledgments
Work supported by ‘Ministero per l’Università e la Ricerca’ (MIUR, Roma; PRIN projects), University of Torino (ex-60% funds), Regione Piemonte, Compagnia di San Paolo (Torino) and Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano).
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Bonetto, A., Penna, F., Minero, V.G. et al. Glutamine prevents myostatin hyperexpression and protein hypercatabolism induced in C2C12 myotubes by tumor necrosis factor-α. Amino Acids 40, 585–594 (2011). https://doi.org/10.1007/s00726-010-0683-3
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DOI: https://doi.org/10.1007/s00726-010-0683-3