Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jun;37(3):441-460.
doi: 10.1007/s10565-020-09558-w. Epub 2020 Oct 9.

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

Lai Wang #  1 , Zu-Guo Zheng #  1 , Lingchang Meng  1 , Lijun Zhu  1 , Ping Li  1 , Jun Chen  2 , Hua Yang  3
Affiliations

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

Lai Wang et al. Cell Biol Toxicol. 2021 Jun.

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.

Keywords: Atrophy; FOXO1; GGPP; IRF4; Myostatin; Simvastatin.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

    1. Ahmadi Y, Ghorbanihaghjo A, Naghi-Zadeh M, Yagin NL. Oxidative stress as a possible mechanism of statin-induced myopathy. Inflammopharmacology. 2018;26(3):667–74. https://doi.org/10.1007/s10787-018-0469-x . - DOI - PubMed
    1. Allen DL, Du M. Comparative functional analysis of the cow and mouse myostatin genes reveals novel regulatory elements in their upstream promoter regions. Comp Biochem Physiol Part B, Biochem Mol Biol. 2008;150(4):432–9. https://doi.org/10.1016/j.cbpb.2008.05.002 . - DOI
    1. Allen DL, Unterman TG. Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am J Physiol Cell Physiol. 2007;292(1):C188–99. https://doi.org/10.1152/ajpcell.00542.2005 . - DOI - PubMed
    1. Barallobre-Barreiro J, Gupta SK, Zoccarato A, Kitazume-Taneike R, Fava M, Yin X, et al. Glycoproteomics reveals decorin peptides with anti-myostatin activity in human atrial fibrillation. Circulation. 2016;134(11):817–32. https://doi.org/10.1161/circulationaha.115.016423 . - DOI - PubMed - PMC
    1. Biesemann N, Mendler L, Wietelmann A, Hermann S, Schafers M, Kruger M, et al. Myostatin regulates energy homeostasis in the heart and prevents heart failure. Circ Res. 2014;115(2):296–310. https://doi.org/10.1161/circresaha.115.304185 . - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources