The role of Merg1a potassium ion channel in skeletal muscle atrophy

Xun Wang, Purdue University

Abstract

Skeletal muscle atrophy is clinically defined as a decrease in muscle mass, strength and endurance, resulting from an imbalance in protein degradation and protein synthesis. Atrophy can be initiated by muscle damage, systemic diseases (e.g., cancer, AIDS), prolonged disuse or starvation and occurs normally with ageing. Most of the accelerated proteolysis that occurs in atrophying muscle appears to be due to activation of the ubiquitin-proteasome pathways. The objective of this study was to investigate the role(s) of the ether-a-go-go related 1 (erg1) in skeletal muscle atrophy. Using western blot and immunohistochemistry, it was revealed that the mouse erg1a (Merg1a) voltage-gated potassium channel is upregulated in the skeletal muscle of mice experiencing atrophy as a result of hindlimb-suspension, cancer cachexia and ageing. Furthermore, ectopic expression of the wild type Merg1a was found to induce a decrease in muscle fiber size (atrophy), ubiquitin-proteasome proteolysis and upregulation of ubiquitin ligases (E3) in weight bearing mice. In contrast, ectopic expression of a dysfunctional mutant erg1 decreased ubiquitin-proteasome proteolysis and blocked the onset of atrophy in hindlimb suspended mice. Additionally, a known Merg1a channel blocker, astemizole, also inhibited the onset of atrophy in hindlimb-suspended mice. These results suggest that erg1 function initiates skeletal muscle atrophy by upregulating the ubiquitin-proteasome proteolytic pathway in skeletal muscle, and that erg1 is therefore a potential drug target for the treatment of muscle atrophy.

Degree

Ph.D.

Advisors

Hannon, Purdue University.

Subject Area

Molecular biology|Anatomy & physiology

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