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

AbstractLiver 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.

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Long Term Adrenal Insufficiency Induces Skeletal Muscle Atrophy and Increases the Serum Levels of Active Form Myostatin in Rat Serum

ZOOLOGICAL SCIENCE ◽

10.2108/zsj.22.229 ◽

2005 ◽

Vol 22 (2) ◽

pp. 229-236 ◽

Cited By ~ 10

Author(s):

Tohru Hosoyama ◽

Chikashi Tachi ◽

Keitaro Yamanouchi ◽

Masugi Nishihara

Keyword(s):

Skeletal Muscle ◽

Adrenal Insufficiency ◽

Muscle Atrophy ◽

Active Form ◽

Serum Levels ◽

Skeletal Muscle Atrophy ◽

Rat Serum

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

10.21203/rs.3.rs-1213317/v1 ◽

2022 ◽

Author(s):

Yohei Shirakami ◽

Junichi Kato ◽

Toshihide Maeda ◽

Takayasu Ideta ◽

Hiroyasu Sakai ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Liver Diseases ◽

Control Diet ◽

Diet Group ◽

Skeletal Muscle Atrophy ◽

Fibrotic Liver ◽

Nash Group ◽

Tnf Α ◽

Senescence Accelerated Mice

Abstract Although liver diseases, including non-alcoholic steatohepatitis (NASH), are associated with skeletal muscle atrophy, the mechanism behind their association has not been fully elucidated. In this study, the effects of aging and NASH on the skeletal muscle and the interaction between the liver and muscle were investigated using a diet-induced NASH model in senescence-accelerated mice (SAM). A total of four groups of SAM and its control mice were fed either an NASH-inducing or control diet. In the SAM/NASH group, the histopathology of NASH and markers of oxidative stress were significant. Skeletal muscles were also markedly atrophied. The expression of the ubiquitin ligase Murf1 in the muscle was significantly increased with muscle atrophy, while that of Tnfa was not significantly different. In contrast, the hepatic Tnfa expression and serum TNF-α levels were significantly increased in the SAM/NASH group. These results suggest that liver-derived TNF-α might promote muscle atrophy associated with steatohepatitis and aging through Murf-1. The metabolomic analysis of skeletal muscle indicated higher spermidine and lower tryptophan levels in the NASH-diet group. The findings of this study revealed an aspect of liver-muscle interaction, which might be important in developing treatments for sarcopenia associated with liver diseases.

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Beneficial effects of GH/IGF-1 on skeletal muscle atrophy and function in experimental heart failure

AJP Cell Physiology ◽

10.1152/ajpcell.00114.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. C138-C144 ◽

Cited By ~ 71

Author(s):

Luciano Dalla Libera ◽

Barbara Ravara ◽

Maurizio Volterrani ◽

Valerio Gobbo ◽

Mila Della Barbera ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Exercise Capacity ◽

Muscle Atrophy ◽

Serum Levels ◽

Skeletal Muscle Atrophy ◽

Gh Treatment ◽

Tnf Α ◽

Myocyte Apoptosis ◽

Contraction And Relaxation

Muscle atrophy is a determinant of exercise capacity in heart failure (CHF). Myocyte apoptosis, triggered by tumor necrosis factor-α (TNF-α) or its second messenger sphingosine (SPH), is one of the causes of atrophy. Growth hormone (GH) improves hemodynamic and cardiac trophism in several experimental models of CHF, but its effect on skeletal muscle in CHF is not yet clear. We tested the hypothesis that GH can prevent skeletal muscle apoptosis in rats with CHF. CHF was induced by injecting monocrotaline. After 2 wk, 2 groups of rats were treated with GH (0.2 mg·kg–1·day–1 and 1.0 mg·kg–1·day–1) subcutaneously. A third group of controls had saline. After 2 additional weeks, rats were killed. Tibialis anterior cross-sectional area, myosin heavy chain (MHC) composition, and a study on myocyte apoptosis and serum levels of TNF-α and SPH were carried out. The number of apoptotic nuclei, muscle atrophy, and serum levels of TNF-α and SPH were decreased with GH at high but not at low doses compared with CHF rats. Bcl-2 was increased, whereas activated caspases and bax were decreased. The MHC pattern in GH-treated animals was similar to that of controls. Monocrotaline slowed down both contraction and relaxation but did not affect specific tetanic force, whereas absolute force was decreased. GH treatment restored contraction and relaxation to control values and brought muscle mass and absolute twitch and tetanic tension to normal levels. These findings may provide an insight into the therapeutic strategy of GH given to patients with CHF to improve exercise capacity.

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