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.
Highlights
Sarcopenia is characterized by low skeletal muscle strength, decreased muscle mass, and low physical performance [1]
The results indicate that DDC hepatotoxin induces chronic liver disease (CLD) independent of Takeda G protein-coupled receptor 5 (TGR5) expression in mice for at least 6 weeks because WT and TGR5−/− mice were affected
Mesocl.oSrcri.e2s0p2o0,n2d1,txoFtOhRe PmEeEaRnR±EVSIEEWM (n = 3, * p < 0.05, two-way ANOVA, Sidak’s multiple compa1r1iosfo2n4 AteNstO).VAAc,cSuidmauk’lsatmivueltfiprelequcoemncpyaraisnoanlytseisst)f.oArcWcuTm(uDla)tiavnedfrTeqGuRen5c−y/−a(nEa)lymsiiscfeowr WerTe tatnedd.TGR5-/- (E) mice wAelrteopgleotthteedr., the results indicate that the DDC diet decreases the fiber diameter in tibial anterior (TA) muscles from WT mice,Abltuotgtehthisere,fftehcetriessluolstst indTicAatme tuhsactlethsefrDoDmCTdGieRt5d−e/−crmeaiscees. the fiber diameter in TA muscles from WT mice, but this effect is lost in TA muscles from TGR5-/- mice. 2.6
Summary
Sarcopenia is characterized by low skeletal muscle strength, decreased muscle mass, and low physical performance [1]. Sarcopenic skeletal muscle shows a decrease in fiber diameter, fiber transition, and reduced content of sarcomeric proteins, such as myosin heavy chain (MHC) and troponin I [4]. Several alterations are observed at the molecular level. One of these is the increased activity and expression of the ubiquitin-proteasome system (UPS), the E3 ubiquitin ligases atrogin-1 and MuRF-1. Sarcopenic muscle likewise develops oxidative stress, characterized by the increased production of reactive oxygen species (ROS) and oxidative-dependent protein modifications, such as the formation of 4-hydroxynonenal (4-HNE) adducts in proteins. Other intracellular events altered in atrophic muscles are mitochondrial dysfunction, autophagy, and myonuclear apoptosis [4,5]
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