Myostatin inhibits proliferation and insulin-stimulated glucose uptake in mouse liver cells.

Watts R, Ghozlan M, Hughey CC, Johnsen VL, Shearer J, Hittel DS
Biochem Cell Biol. 2014 92 (3): 226-34

PMID: 24882465 · DOI:10.1139/bcb-2014-0004

Although myostatin functions primarily as a negative regulator of skeletal muscle growth and development, accumulating biological and epidemiological evidence indicates an important contributing role in liver disease. In this study, we demonstrate that myostatin suppresses the proliferation of mouse Hepa-1c1c7 murine-derived liver cells (50%; p < 0.001) in part by reducing the expression of the cyclins and cyclin-dependent kinases that elicit G1-S phase transition of the cell cycle (p < 0.001). Furthermore, real-time PCR-based quantification of the long noncoding RNA metastasis associated lung adenocarcinoma transcript 1 (Malat1), recently identified as a myostatin-responsive transcript in skeletal muscle, revealed a significant downregulation (25% and 50%, respectively; p < 0.05) in the livers of myostatin-treated mice and liver cells. The importance of Malat1 in liver cell proliferation was confirmed via arrested liver cell proliferation (p < 0.05) in response to partial Malat1 siRNA-mediated knockdown. Myostatin also significantly blunted insulin-stimulated glucose uptake and Akt phosphorylation in liver cells while increasing the phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS), a protein that is essential for cancer cell proliferation and insulin-stimulated glucose transport. Together, these findings reveal a plausible mechanism by which circulating myostatin contributes to the diminished regenerative capacity of the liver and diseases characterized by liver insulin resistance.

MeSH Terms (17)

Animals Antineoplastic Agents Cell Proliferation Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Glucose Insulin Liver Male Mice Mice, Inbred C57BL Myostatin Phosphorylation Proto-Oncogene Proteins c-akt RNA, Long Noncoding Structure-Activity Relationship Tumor Cells, Cultured

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