Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway.
Skeletal muscle atrophy results from an imbalance in protein degradation and protein synthesis and occurs in response to injury, various disease states, disuse, and normal aging. Current treatments for this debilitating condition are inadequate. More information about mechanisms involved in the onset and progression of muscle atrophy is necessary for development of more effective therapies. Here we show that expression of the mouse ether-a-go-go related gene (Merg1a) K+ channel is up-regulated in skeletal muscle of mice experiencing atrophy as a result of both malignant tumor expression and disuse. Further, ectopic expression of Merg1a in vivo induces atrophy in healthy wt-bearing mice, while expression of a dysfunctional Merg1a mutant suppresses atrophy in hindlimb-suspended mice. Treatment of hindlimb-suspended mice with astemizole, a known Merg1a channel blocker, inhibits atrophy in these animals. Importantly, in vivo expression of Merg1a in mouse skeletal muscle activates the ubiquitin proteasome pathway that is responsible for the majority of protein degradation that causes muscle atrophy, yet expression of a dysfunctional Merg1a mutant decreases levels of ubiquitin-proteasome proteolysis. Thus, expression of Merg1a likely initiates atrophy by activating ubiquitin-proteasome proteolysis. This gene and its product are potential targets for prevention and treatment of muscle atrophy.
Wang
Xun
X
Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, 625 Harrison St., West Lafayette, Indiana 47907, USA.
Hockerman
Gregory H
GH
Green
Henry W
HW
Babbs
Charles F
CF
Mohammad
Sulma I
SI
Gerrard
David
D
Latour
Mickey A
MA
London
Barry
B
Hannon
Kevin M
KM
Pond
Amber L
AL
D000818:Animals; D001284:Atrophy; D001921:Brain / Q000502:physiology; D000072237:ERG1 Potassium Channel; D004938:Esophageal Neoplasms; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology*; D006614:Hindlimb; D006801:Humans; D007624:KB Cells; D051379:Mice; D018482:Muscle, Skeletal / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D016474:Weight-Bearing
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex