FGF19 protects skeletal muscle against obesity‐induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT‐1/PGC‐α pathway

Abstract

Obesity is associated with biological dysfunction in skeletal muscle. As a condition of obesity accompanied by muscle mass loss and physical dysfunction, sarcopenic obesity (SO) has become a novel public health problem. Human fibroblast growth factor 19 (FGF19) plays a therapeutic role in metabolic diseases. However, the protective effects of FGF19 on skeletal muscle in obesity and SO are still not completely understood. Our results showed that FGF19 administration improved muscle loss and grip strength in young and aged mice fed a high‐fat diet (HFD). Increases in muscle atrophy markers (FOXO‐3, Atrogin‐1, MuRF‐1) were abrogated by FGF19 in palmitic acid (PA)‐treated C2C12 myotubes and in the skeletal muscle of HFD‐fed mice. FGF19 not only reduced HFD‐induced body weight gain, excessive lipid accumulation and hyperlipidaemia but also promoted energy expenditure (PGC‐1α, UCP‐1, PPAR‐γ) in brown adipose tissue (BAT). FGF19 treatment restored PA‐ and HFD‐induced hyperglycaemia, impaired glucose tolerance and insulin resistance (IRS‐1, GLUT‐4) and mitigated the PA‐ and HFD‐induced decrease in FNDC‐5/irisin expression. However, these beneficial effects of FGF19 on skeletal muscle were abolished by inhibiting AMPK, SIRT‐1 and PGC‐1α expression. Taken together, this study suggests that FGF19 protects skeletal muscle against obesity‐induced muscle atrophy, metabolic derangement and abnormal irisin secretion partially through the AMPK/SIRT‐1/PGC‐α signalling pathway, which might be a potential therapeutic target for obesity and SO.

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“…Grip strength was measured by using an electronic grip strength metre (Cat. 47200, Ugo Basil) as described previously 21 . The grip index is reported as grip strength divided by body weight.…”

“…The grip index is reported as grip strength divided by body weight. Body composition was measured as described previously 21 by dual-energy X-ray absorptiometry (DEXA, Hologic Discovery A, Hologic Inc) (n=5).…”

“…GAS sections were stained with haematoxylin and eosin (H&E) and Masson trichrome, as described previously 22 . Frozen sections were stained with Oil-red O 21 . The average cross-sectional area (CSA), fibrosis, and Oil-red O-positive area of GAS myofibres were measured and analyzed by ImageJ software (NIH, USA).…”

The Saga of Endocrine FGFs

“…Additionally, treatment with recombinant FGF19 increased the myotube area in human muscle cells during differentiation from myoblast to myotube, as well as in fully differentiated myotube [ 89 ]. Recently, Guo et al (2021) demonstrated the role of FGF19 in regulating skeletal muscle of mice by enlarging muscle fiber size as well as detailed a mechanism for such function [ 90 ]. Specifically, FGF19 increases the muscle fiber size by stimulating the phosphorylation of the ERK 1 and 2 and S6K1 pathways [ 90 ].…”

“…Recently, Guo et al (2021) demonstrated the role of FGF19 in regulating skeletal muscle of mice by enlarging muscle fiber size as well as detailed a mechanism for such function [ 90 ]. Specifically, FGF19 increases the muscle fiber size by stimulating the phosphorylation of the ERK 1 and 2 and S6K1 pathways [ 90 ]. Furthermore, they also showed that FGF19 was able to protect the skeletal muscle against obesity-induced muscle atrophy through the AMP-activated protein kinase (AMPK)-Sirtuin-1 (SIRT1)-PGC1α pathway, which may be a potential target for obesity treatment [ 90 ].…”