Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor
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Skeletal muscle atrophy is characterized by the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. An increase in the expression of two muscle-specific E3 ligases, atrogin-1 and MuRF-1, and oxidative stress are involved in muscle atrophy. Patients with chronic liver diseases (CLD) develop muscle wasting. Several bile acids increase in plasma during cholestatic CLD, among them, cholic acid (CA) and deoxycholic acid (DCA). The receptor for bile acids, TGR5, is expressed in healthy skeletal muscles. TGR5 is involved in the regulation of muscle differentiation and metabolic changes. In this paper, we evaluated the participation of DCA and CA in the generation of an atrophic condition in myotubes and isolated fibers from the muscle extracted from wild-type (WT) and TGR5-deficient (TGR5(-/-)) male mice. The results show that DCA and CA induce a decrease in diameter, and myosin heavy chain (MHC) protein levels, two typical atrophic features in C2C12 myotubes. We also observed similar results when INT-777 agonists activated the TGR5 receptor. To evaluate the participation of TGR5 in muscle atrophy induced by DCA and CA, we used a culture of muscle fiber isolated from WT and TGR5(-/-) mice. Our results show that DCA and CA decrease the fiber diameter and MHC protein levels, and there is an increase in atrogin-1, MuRF-1, and oxidative stress in WT fibers. The absence of TGR5 in fibers abolished all these effects induced by DCA and CA. Thus, we demonstrated that CS and deoxycholic acid induce skeletal muscle atrophy through TGR5 receptor.
BASAL Grant CEDENNA AFB180001 Programa de Cooperacion Cientifica ECOS-CONICYT C16S02 Millennium Institute on Immunology and Immunotherapy P09-016-F Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) 21161353 Nucleus of Ion ChannelsAssociated Diseases MiNICAD Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) AFB170005 National Fund for Science and Technological Development Fondecyt 11171001 Fondecyt 1161288 Fondecyt 1161646
Artículo de publicación ISI
Quote ItemJ Cell Physiol. 2020;1–13
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