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Statins induce skeletal muscle atrophy via GGPP depletion-dependent myostatin overexpression in skeletal muscle and brown adipose tissue

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Abstract

Myopathy is the major adverse effect of statins. However, the underlying mechanism of statin-induced skeletal muscle atrophy, one of statin-induced myopathy, remains to be elucidated. Myostatin is a negative regulator of skeletal muscle mass and functions. Whether myostatin is involved in statin-induced skeletal muscle atrophy remains unknown. In this study, we uncovered that simvastatin administration increased serum myostatin levels in mice. Inhibition of myostatin with follistatin, an antagonist of myostatin, improved simvastatin-induced skeletal muscle atrophy. Simvastatin induced myostatin expression not only in skeletal muscle but also in brown adipose tissue (BAT). Mechanistically, simvastatin inhibited the phosphorylation of forkhead box protein O1 (FOXO1) in C2C12 myotubes, promoting the nuclear translocation of FOXO1 and thereby stimulating the transcription of myostatin. In differentiated brown adipocytes, simvastatin promoted myostatin expression mainly by inhibiting the expression of interferon regulatory factor 4 (IRF4). Moreover, the stimulative effect of simvastatin on myostatin expression was blunted by geranylgeranyl diphosphate (GGPP) supplementation in both myotubes and brown adipocytes, suggesting that GGPP depletion was attributed to simvastatin-induced myostatin expression. Besides, the capacities of statins on stimulating myostatin expression were positively correlated with the lipophilicity of statins. Our findings provide new insights into statin-induced skeletal muscle atrophy.

Graphical headlights

1. Simvastatin induces skeletal muscle atrophy via increasing serum myostatin levels in mice;

2. Simvastatin promotes myostatin expression in both skeletal muscle and brown adipose tissue through inhibiting GGPP production;

3. The stimulating effect of statins on myostatin expression is positively correlated with the lipophilicity of statins.

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Abbreviations

CK:

Creatine kinase

HMG-CoA:

3-hydroxy-3-methyl-glutaryl-coenzyme A

SAMS:

Statin-associated muscle symptoms

GDF8:

Growth differentiation factor 8

TGF-β:

Transforming growth factor β

BAT:

Brown adipose tissue

FOXO1:

Forkhead box protein O1

IRF4:

Interferon regulatory factor 4

UCP1:

Uncoupling protein 1

GGPP:

Geranylgeranyl diphosphate

FPP:

Farnesyl pyrophosphate

FBS:

Fetal bovine serum

NBS:

New bovine serum

PFA:

Paraformaldehyde

BSA:

Bovine serum albumin

DAPI:

4′, 6-diamidino-2-phenylindole

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Funding

This work was supported by the National Key R&D Program of China (2019YFC1711000), National Natural Science Foundation of China (81722048), and “Double First-Class” University project (CPU2018GY09).

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Correspondence to Jun Chen or Hua Yang.

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The authors declare that they have no conflict of interests.

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The manuscript does not contain clinical studies or participant data.

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Wang, L., Zheng, ZG., Meng, L. et al. Statins induce skeletal muscle atrophy via GGPP depletion-dependent myostatin overexpression in skeletal muscle and brown adipose tissue. Cell Biol Toxicol 37, 441–460 (2021). https://doi.org/10.1007/s10565-020-09558-w

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  • DOI: https://doi.org/10.1007/s10565-020-09558-w

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