Chchd10 is dispensable for myogenesis but critical for adipose browning

The Chchd10 gene encodes a coiled-coil-helix-coiled-coil-helix-domain containing protein predicted to function in the mitochondrion and nucleus.Mutations of Chchd10 are associated with ALS,dementia and myopathy in humans and animal models,but how knockout of Chchd10(Chchd10KO)affects various tissues especially skeletal muscle and adipose tissues remains unclear.Here we show that Chchd10 expression increases as myoblasts and preadipocytes dif-ferentiate.During myogenesis,CHCHD10 interacts with TAR DNA binding protein 43(TDP-43)in regenerating myofib-ers in vivo and in newly differentiated myotubes ex vivo.Surprisingly,Chchd10KO mice had normal skeletal muscle development,growth and regeneration,with moderate defects in grip strength and motor performance.Chchd10KO similarly had no effects on development of brown and white adipose tissues(WAT).However,Chchd10KO mice had blunted response to acute cold and attenuated cold-induced browning of WAT,with markedly reduced UCP1 levels.Together,these results demonstrate that Chchd10 is dispensable for normal myogenesis and adipogenesis but is required for normal motility and cold-induced,mitochondrion-dependent browning of adipocytes.The data also sug-gest that human CHCHD10 mutations cause myopathy through a gain-of-function mechanism.

Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis

Background and aims:Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis(NASH)treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients.Recently,we have shown that combining a gut-restricted apical sodium-bile acid transporter(ASBT)inhibitor GSK2330672(GSK)with adeno-associated virus(AAV)-mediated liver fibroblast growth factor 15(FGF15)overexpression provides significantly improved efficacy than either single treatment against NASH and liver fibrosis in a high fat,cholesterol,and fructose(HFCFr)diet-induced NASH mouse model.The beneficial effects of the com-bined treatment can be attributed to the markedly reduced bile acid pool that reduces liver bile acid burden and intestinal lipid absorption.The aim of this study is to further investigate if combining GSK treatment with the orally bioavailable obeticholic acid(OCA),which induces endogenous FGF15 and inhibits hepatic bile acid synthesis,can achieve similar anti-NASH effect as the GSKþAAV-FGF15 co-treatment in HFCFr-diet-fed mice.Materials and methods:Male C57BL/6J mice were fed HFCFr diet to induce NASH and liver fibrosis.The effect of GSK,OCA,and GSKþOCA treatments on NASH development was compared and contrasted among all groups.Results:Findings from this study showed that the GSKþOCA co-treatment did not cause persistent reduction of obesity over a 12-week treatment period.Neither single treatment nor the GSKþOCA co-treatment reduce hepatic steatosis,but all three treatments reduced hepatic inflammatory cytokines and fibrosis by a similar magnitude.The GSKþOCA co-treatment caused a higher degree of total bile acid pool reduction(~55%)than either GSK or OCA treatment alone.However,such bile acid pool reduction was insufficient to cause increased fecal lipid loss.The GSKþOCA co-treatment prevented GSK-mediated induction of hepatic cholesterol 7alpha-hydroxylase but failed to induce ileal FGF15 expression.GSK did not reduce gallbladder OCA amount in the GSKþOCA group compared to the OCA group,suggesting that ASBT inhibition does not reduce hepatic OCA distribution.Conclusions:Unlike the GSKþAAV-FGF15 co-treatment,the GSKþOCA co-treatment does not provide improved efficacy against NASH and liver fibrosis than either single treatment in mice.The lack of synergistic effect may be partly attributed to the moderate reduction of total bile acid pool and the lack of high level of FGF15 exposure as seen in the GSKþAAV-FGF15 co-treatment.