Myostatin promotes liver fat accumulation through activation of the mTOR-SREBP-1c pathway
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Myostatin is a cytokine primarily expressed in skeletal muscle and heart muscle and acts as a negative regulator for muscle development. Inhibition of myostatin by genetic and pharmacological approaches improves metabolic health, which has been generally considered as secondary to the hypermuscularity and insulin hyper-sensitivity. Although the receptor for myostatin is ubiquitously expressed, whether and how myostatin interacts with other metabolically important cell types remain largely unknown. In this work, we provide multiple lines of evidence that myostatin directly interacts with hepatocytes. Furthermore, we show for the first time that myostatin enhances insulin signaling in both cultured hepatocytes and in mouse liver. Mice injected with adena-associated virus encoding myostatin propeptide, an endogenous myostatin inhibitor, were partially protected from diet-induced liver fat accumulation and reduced lipogenic gene expression. Consistent with the in vivo findings, increased lipid accumulation was found in cells treated with myostatin peptide or transfected with myostatin construct. Myostatin promotes the lipogenic effect of insulin by enhancing nuclear translocation of SREBP-1c, the master lipogenic transcription factor and increases expression of its downstream target genes. This effect was found to be associated with myostatin-related mTOR activation. Blocking mTOR activation by rapamycin prevents myostatinassociated increase of nuclear SREBP-1 c and its downstream lipogenic enzymes. In summary, this work identified liver as a direct target of myostatin, providing the first evidence that myostatin has opposite impacts on insulin signaling in muscle cells and hepatocytes. Our data also provided a novel mechanism for the long-term metabolic protection afforded by anti-myostatin treatments demonstrated in this work as well as elsewhere.
Thesis (M.A.)--Boston University
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