Deficiency of fibroblast growth factor 21 aggravates obesity-induced atrophic responses in skeletal muscle

Chu-Sook Kim,Eun Roh,Yeonsoo Joe,Hye-Seon Choi,Tae Youl Ha,Hun Taeg Chung,Sung Hoon Back,Min-Seon Kim,Jeong Woo Park,Rina Yu

doi:10.1186/s12950-019-0221-3

Abstract

BackgroundObesity-induced skeletal muscle inflammation is a major contributor of skeletal muscle loss/atrophy and is implicated in metabolic complications such as insulin resistance. Fibroblast growth factor 21 (FGF21) is known to be an important metabolic regulator with anti-inflammatory properties. However, the effect of FGF21 on skeletal muscle atrophy is unclear. In this study, we investigated the effect of FGF21 deficiency on obesity-induced skeletal muscle inflammation and atrophy in mice.ResultsThe expression of atrophic factors (MuRF1 and Atrogin-1) was upregulated at the mRNA and/or protein levels in the skeletal muscle of FGF21-deficient obese mice compared with wild type obese control mice. This was accompanied by an increase in levels of inflammatory cytokines (TNFα and MCP-1) and a reduction in AMPK phosphorylation. FGF21 treatment markedly suppressed TNFα-mediated inflammatory and atrophic responses in cultured myotubes, and the actions of FGF21 were blunted by the AMPK inhibitor compound C.ConclusionThese findings suggest that FGF21 deficiency aggravates obesity-induced inflammation and atrophic responses in the skeletal muscle of obese mice, and FGF21 may protect inflammation-mediated atrophy through the AMPK pathway.

Highlights

Obesity-induced skeletal muscle inflammation is a major contributor of skeletal muscle loss/atrophy and is implicated in metabolic complications such as insulin resistance
Knockout of Fibroblast growth factor 21 (FGF21) induces atrophic responses in the skeletal muscle of highfat diet (HFD)-fed mice In this study, we examined whether absence of FGF21 induces an obesity-induced atrophic response in skeletal muscle
Western blot analysis revealed that the levels of atrophic proteins (MuRF1 and Atrogin-1) were increased in the HFD-fed FGF21-deficient mice compared to the HFD-fed WT mice (Fig. 1e)

Summary

Introduction

Obesity-induced skeletal muscle inflammation is a major contributor of skeletal muscle loss/atrophy and is implicated in metabolic complications such as insulin resistance. Fibroblast growth factor 21 (FGF21) is known to be an important metabolic regulator with anti-inflammatory properties. We investigated the effect of FGF21 deficiency on obesity-induced skeletal muscle inflammation and atrophy in mice. Obesity is closely associated with loss/atrophy of skeletal muscle mass referred to as sarcopenia, which contributes to frailty/physical disability [1, 2] and metabolic complications such as insulin resistance and type 2 diabetes [3]. Obesity-induced skeletal muscle inflammation, characterized by increased levels of inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), promotes an imbalance in muscle protein synthesis and degradation leading to muscle atrophy [4]. FGF21 promotes weight loss through an increase in fatty acid oxidation and

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