Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communication
Hui Wang, … , Tiemin Liu, Xingxing Kong
Hui Wang, … , Tiemin Liu, Xingxing Kong
Published June 18, 2024
Citation Information: J Clin Invest. 2024;134(16):e178303. https://doi.org/10.1172/JCI178303.
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Research Article Endocrinology

Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communication

Abstract

Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than did controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-Seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablated BAT. Further studies demonstrated that Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, whereas fibroblast growth factor 21 (FGF21) contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN/SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocyte–derived MSTN regulated BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.

Authors

Hui Wang, Shanshan Guo, Huanqing Gao, Jiyang Ding, Hongyun Li, Xingyu Kong, Shuang Zhang, Muyang He, Yonghao Feng, Wei Wu, Kexin Xu, Yuxuan Chen, Hanyin Zhang, Tiemin Liu, Xingxing Kong

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Figure 3

MSTN ablation in BAT impairs the function of skeletal muscle.

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MSTN ablation in BAT impairs the function of skeletal muscle. (A) Grip s...
(A) Grip strength of male Flox and BKO mice on a HFD (n = 7–11). (B) Total distance achieved by male Flox and BKO mice on a HFD in the exhaustion test (n = 6–8). (C) Latency (Lat) of compound muscle action potentials in GAS muscles of mice (n = 4–6). (D) OCR in GAS muscles from BKO and Flox mice on a HFD (n = 6). ADP, adenosine diphosphate); PMG, pyruvate, malate, glutamine; CYC, cytochrome C; SUC, succinate; FCCP, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; ROT, rotenone; AMA, antimycin A. (E) Immunofluorescence analysis of fiber type composition in GAS. The different myosin heavy chain isoforms are stained in blue (MyHC-I), green (MyHC-IIA), or red (MyHC-IIB). Scale bars: 50 μm. (F) Representative H&E staining of GAS from BKO and Flox mice on a HFD. Scale bars: 50 μm. (G) Fiber CSA distribution and median CSA of GAS. (H) Representative H&E staining of TA tissue, 3 days, 5 days, 7 days, and 28 days after CTX injury. Scale bars: 50 μm. (I) TG levels in GAS from BKO and Flox mice on a 12-week HFD (n = 6–8). dpi, days post injection. (J) Representative Oil Red O staining of GAS muscle from BKO and Flox mice on a HFD. Scale bars: 50 μm. (K) Representative electron micrographs of lipid droplets in muscle from male mice. Scale bars: 1 μm. (L) Heatmap of 323 DEGs of GAS from BKO and Flox mice on a HFD. up, upregulated; down, downregulated. (M and N) KEGG analysis and GSEA based on downregulated genes. (O) Relative mRNA expression of lipid metabolism–related genes in GAS of BKO and Flox mice on a 12-week HFD (n = 5). (P) Relative mRNA expression of lipid metabolism related genes in GAS of AAV8-sgCon and AAV8-sgMstn mice on a 12-week HFD (n = 3). All results are shown as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-tailed Student’s t test.