Liver fibrosis-induced muscle atrophy is mediated by elevated levels of circulating TNFα

Abstract

Liver cirrhosis is a critical health problem associated with several complications, including skeletal muscle atrophy, which adversely affects the clinical outcome of patients independent of their liver functions. However, the precise mechanism underlying liver cirrhosis-induced muscle atrophy has not been elucidated. Here we show that serum factor induced by liver fibrosis leads to skeletal muscle atrophy. Using bile duct ligation (BDL) model of liver injury, we induced liver fibrosis in mice and observed subsequent muscle atrophy and weakness. We developed culture system of human primary myotubes that enables an evaluation of the effects of soluble factors on muscle atrophy and found that serum from BDL mice contains atrophy-inducing factors. This atrophy-inducing effect of BDL mouse serum was mitigated upon inhibition of TNFα signalling but not inhibition of myostatin/activin signalling. The BDL mice exhibited significantly up-regulated serum levels of TNFα when compared with the control mice. Furthermore, the mRNA expression levels of Tnf were markedly up-regulated in the fibrotic liver but not in the skeletal muscles of BDL mice. The gene expression analysis of isolated nuclei revealed that Tnf is exclusively expressed in the non-fibrogenic diploid cell population of the fibrotic liver. These findings reveal the mechanism through which circulating TNFα produced in the damaged liver mediates skeletal muscle atrophy. Additionally, this study demonstrated the importance of inter-organ communication that underlies the pathogenesis of liver cirrhosis.

Skeletal muscle atrophy is exacerbated by steatotic and fibrotic liver‐derived TNF‐α in senescence‐accelerated mice

“…6). As was also suggested by a previous report 30 , this liver-muscle crosstalk has clinical signi cance because TNF-α is considered as one of the essential factors for skeletal muscle atrophy promoted by hepatic diseases, and this circulating cytokine can be a potential target for the prevention and treatment of NAFLD/NASH-associated skeletal muscle atrophy. Abbreviations ALT, alanine aminotransferase; ANOVA, analysis variance; CDAHFD, choline-de cient, L-amino acidde ned, high-fat diet; CE-TOFMS, capillary electrophoresis time-of-ight mass spectrometry; CE-QqQMS, capillary electrophoresis-triple quadrupole mass spectrometry; FoxO, forkhead box-containing protein; HCA, hierarchical cluster analysis; HE, hematoxylin and eosin; IGF, insulin-like growth factor; NAFLD, nonalcoholic fatty liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis; PCA, principal component analysis; qRT-PCR, quantitative transcription PCR; SAM, senescence-accelerated mouse; SAMP, senescence-accelerated mouse prone; SAMR, senescenceaccelerated mouse resistant; TNF, tumour necrosis factor; 8-OHdG, 8-hydroxy-2'-deoxyguanosine Declarations Figures…”

“…The role of TNF‐α in skeletal muscle atrophy has been extensively investigated 27–32 . One study demonstrated that TNF‐α produced in fibrotic liver was transported to muscle through the bloodstream, leading to atrophy of skeletal muscle.…”

Skeletal Muscle Atrophy is Exacerbated By Steatotic and Fibrotic Liver-Derived TNF-Alpha in Senescence-Accelerated Mice

“…6). As was also suggested by a previous report 30 , this liver-muscle crosstalk has clinical signi cance because TNF-α is considered as one of the essential factors for skeletal muscle atrophy promoted by hepatic diseases, and this circulating cytokine can be a potential target for the prevention and treatment of NAFLD/NASH-associated skeletal muscle atrophy. Abbreviations ALT, alanine aminotransferase; ANOVA, analysis variance; CDAHFD, choline-de cient, L-amino acidde ned, high-fat diet; CE-TOFMS, capillary electrophoresis time-of-ight mass spectrometry; CE-QqQMS, capillary electrophoresis-triple quadrupole mass spectrometry; FoxO, forkhead box-containing protein; HCA, hierarchical cluster analysis; HE, hematoxylin and eosin; IGF, insulin-like growth factor; NAFLD, nonalcoholic fatty liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis; PCA, principal component analysis; qRT-PCR, quantitative transcription PCR; SAM, senescence-accelerated mouse; SAMP, senescence-accelerated mouse prone; SAMR, senescenceaccelerated mouse resistant; TNF, tumour necrosis factor; 8-OHdG, 8-hydroxy-2'-deoxyguanosine…”

Tricarboxylic acid (TCA) cycle, sphingolipid, and phosphatidylcholine metabolism are dysregulated inT. gondiiinfection-induced cachexia

“…Patients with chronic liver disease have reduced muscle mass 48 . Kurosawa et al used the bile duct ligation model of liver injury to demonstrate a causal relationship between liver fibrosis and muscle wasting 49 , highlighting the importance of liver function in systemic metabolism. Defective lipid metabolism in the liver is becoming accepted as a contributor to peripheral tissue wasting in cancer cachexia 18 , underlining the importance of lipid metabolism in the pathology of cachexia.…”