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

Abstract

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.

Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: A randomized, controlled trial

“…SGLT2i is reportedly involved in reducing liver fat and ALT levels in patients with type 2 diabetes and non‐alcoholic fatty liver disease. Although the mechanistic details underlying the beneficial effects of SGLT2i on liver function have not been clarified, a preclinical study found deleterious effects of myostatin on hepatocytes, such as inhibition of proliferation and insulin‐stimulated glucose uptake. The present study confirmed that dapagliflozin reduced myostatin levels and improved γ‐GTP levels compared with control treatment in type 2 diabetes patients.…”

Micromanagement of Immune System: Role of miRNAs in Helminthic Infections

“…Apart from this, they also found striking similarities between fhe-mir-2b-A and fhe-mir-2a-B and the two mir-27 orthologs, bta-mir-27a and bta-mir-27b, these two are known to target the 3′ un-translated region (UTR) of myostatin and insulin growth factor (IGF) in cattle and human (Miretti et al, 2013). While myostatin down-regulation has been associated with increased liver cell proliferation (Watts et al, 2014) and the decreased of has been associated with increased cancer risk (Loumaye et al, 2015). …”

The revised microRNA complement of Fasciola hepatica reveals a plethora of overlooked microRNAs and evidence for enrichment of immuno-regulatory microRNAs in extracellular vesicles

“…S1). Both are known to target the 3 0 untrans-171 lated region (UTR) of myostatin and insulin growth factor (IGF) 172 in cattle and human(Miretti et al, 2013), where myostatin down-173 regulation has been shown to increase liver cell proliferation 174(Watts et al, 2014) and the decrease of IGF -which is also targeted 175 by the highly expressed mir-190 orthologue -has been associated 176 with increased cancer risk(Arnaldez and Helman, 2012). Of the 177 total seven mir-2s in F. hepatica, these two miRNAs and their iso-178 forms show in total 11 conserved sites (in both datasets the highly 179 expressed fhe-mir-2c-B shows 13), that might allow the mir-27a/b 180 to target myostatin (Supplementary Fig.…”