Local overexpression of the myostatin propeptide increases glucose transporter expression and enhances skeletal muscle glucose disposal

Cleasby, M E; Jarmin, S; Eilers, W; Elashry, M; Andersen, D K; Dickson, G; Foster, K

Abstract

Insulin resistance (IR) in skeletal muscle is a prerequisite for type 2 diabetes and is often associated with obesity. IR also develops alongside muscle atrophy in older individuals in sarcopenic obesity. The molecular defects that underpin this syndrome are not well characterized, and there is no licensed treatment. Deletion of the transforming growth factor-β family member myostatin, or sequestration of the active peptide by overexpression of the myostatin propeptide/latency-associated peptide (ProMyo) results in both muscle hypertrophy and reduced obesity and IR. We aimed to establish whether local myostatin inhibition would have a paracrine/autocrine effect to enhance glucose disposal beyond that simply generated by increased muscle mass, and the mechanisms involved. We directly injected adeno-associated virus expressing ProMyo in right tibialis cranialis/extensor digitorum longus muscles of rats and saline in left muscles and compared the effects after 17 days. Both test muscles were increased in size (by 7 and 11%) and showed increased radiolabeled 2-deoxyglucose uptake (26 and 47%) and glycogen storage (28 and 41%) per unit mass during an intraperitoneal glucose tolerance test. This was likely mediated through increased membrane protein levels of GLUT1 (19% higher) and GLUT4 (63% higher). Interestingly, phosphorylation of phosphoinositol 3-kinase signaling intermediates and AMP-activated kinase was slightly decreased, possibly because of reduced expression of insulin-like growth factor-I in these muscles. Thus, myostatin inhibition has direct effects to enhance glucose disposal in muscle beyond that expected of hypertrophy alone, and this approach may offer potential for the therapy of IR syndromes.

Citation

Cleasby, M. E., Jarmin, S., Eilers, W., Elashry, M., Andersen, D. K., Dickson, G., & Foster, K. (2014). Local overexpression of the myostatin propeptide increases glucose transporter expression and enhances skeletal muscle glucose disposal. https://doi.org/10.1152/ajpendo.00586.2013

• Journal Article Type: Article
• Acceptance Date: Jan 28, 2014
• Publication Date: Apr 1, 2014
• Deposit Date: Nov 11, 2014
• Publicly Available Date: Sep 17, 2018
• Journal: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
• Peer Reviewed: Peer Reviewed
• Volume: 306
• Issue: 7
• Pages: E814-E823
• DOI: https://doi.org/10.1152/ajpendo.00586.2013
• Public URL: https://rvc-repository.worktribe.com/output/1405765
• Additional Information: Corporate Creators : London, Reading