title: 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.
authors.affiliation: a Faculty of Kinesiology, University of Calgary, 2500 University Dr. Calgary, AB T2N 1N4, Canada.
authors.forename: Rani
authors.initials: R
authors.lastname: Watts
authors.forename: Mostafa
authors.initials: M
authors.lastname: Ghozlan
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Hughey
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Johnsen
authors.forename: Jane
authors.initials: J
authors.lastname: Shearer
authors.forename: Dustin S
authors.initials: DS
authors.lastname: Hittel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055435:Myostatin / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007328:Insulin; C557040:Malat1 long non-coding RNA, mouse; D055435:Myostatin; D062085:RNA, Long Noncoding; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Malat1 siRNA; cell cycle; cycle cellulaire; glucose metabolism; hepatogenesis; hépatogenèse; myostatin; myostatine; métabolisme du glucose; pARNi de Malat1