Sarcopenia Induced by Chronic Liver Disease in Mice Requires the Expression of the Bile Acids Membrane Receptor TGR5

Abstract

Sarcopenia is a condition of muscle dysfunction, commonly associated with chronic liver disease (CLD), characterized by a decline in muscle strength, the activation of the ubiquitin-proteasome system (UPS), and oxidative stress. We recently described a murine model of CLD-induced sarcopenia by intake of hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which presents an increase in plasma bile acids (BA). BA induced skeletal muscle atrophy through a mechanism dependent on the Takeda G protein-coupled receptor 5 (TGR5) receptor. In the present study, we evaluated the role of TGR5 signaling in the development of sarcopenia using a model of DDC-induced CLD in C57BL6 wild-type (WT) mice and mice deficient in TGR5 expression (TGR5−/− mice). The results indicate that the decline in muscle function and contractibility induced by the DDC diet is dependent on TGR5 expression. TGR5 dependence was also observed for the decrease in fiber diameter and sarcomeric proteins, as well as for the fast-to-slow shift in muscle fiber type. UPS overactivation, indicated by increased atrogin-1/MAFbx (atrogin-1) and muscle RING-finger protein-1 (MuRF-1) protein levels and oxidative stress, was abolished in tibialis anterior muscles from TGR5−/− mice. Our results collectively suggest that all sarcopenia features induced by the DDC-supplemented diet in mice are dependent on TGR5 receptor expression.

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

“…Together, these results suggest that high serum concentrations of BA induce hepatic oxidative stress. 5 Oxidative Medicine and Cellular Longevity Our laboratory described the induction of sarcopenia in a mice model of cholestatic liver disease characterized by TGR5-dependent mechanisms: (1) oxidative stress, presenting elevated ROS, carbonylated proteins, and 4-HNE in skeletal muscles; (2) increased myonuclear apoptosis, with induction of the caspase pathway and increased Bax/Bcl-2 ratio; and (3) induction of protein catabolism through UPS [54,107,109]. Interestingly, ROS is directly associated with the UPS induction and mitochondrial alterations that might induce apoptosis [108,[110][111][112].…”

“…Recently, our group demonstrated that DCA and CA, in a TGR5-dependent manner, induced sarcopenia and atrophy in skeletal muscle by incrementing the ubiquitin-proteasome system (UPS) and oxidative stress [ 44 ]. Also, the absence of the TGR5 receptor prevents the sarcopenia induced by cholestatic chronic liver disease, protecting the muscle from loss of mass and strength [ 54 ]. These results contradict a report indicating that TGR5 enhances muscle differentiation in the C2C12 myoblast and induces hypertrophy in mice [ 45 ].…”

“…This change induces the inhibition of ileal FXR signaling with the consequent decrease in serum levels of FGF15, an enterokine related to muscle wasting [ 113 ]. Considering the antecedents related to muscular TGR5, BA, and sarcopenia [ 44 , 54 ], it is impossible to discard this receptor's participation in the muscle dysfunction associated with alteration in the microbiota-BA axis.…”

Gut microbiota in sarcopenia and heart failure

“…Therefore, GMM that can modulate inflammation signaling pathways, such as SCFAs, can affect normal skeletal muscle metabolism and cause muscle wasting. Indeed, various studies have been demonstrated that SCFAs play a profound role in regulating muscle mass and physical function [131] . There are studies that suggest that liver disease, which causes abnormal production of BAs, may lead to muscle wasting and cachexia [132,133] .…”

“…Indeed, various studies have been demonstrated that SCFAs play a profound role in regulating muscle mass and physical function [ 131 ] . There are studies that suggest that liver disease, which causes abnormal production of BAs, may lead to muscle wasting and cachexia [ 132 , 133 ] . However, currently, there is no study evaluating the GMM-BAs associated with sarcopenia.…”