Mergla K ⁺ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway

Abstract

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.

Extracellular signal-regulated kinase pathway is differentially involved in β-agonist-induced hypertrophy in slow and fast muscles

“…To test whether blocking of MAPK signaling would reverse BA-induced muscle fiber hypertrophy in vivo, we electroporated the EGFPtagged MKP-1 plasmid into mouse lateral gastrocnemius muscles, where fibers are primarily type IIb. We have shown that neither electroporation itself nor overexpression of the control plasmid ␤-Gal (LacZ) has no effect on muscle fiber crosssectional area (1,44). Clenbuterol induced the hypertrophy of these IIb fibers, as indicated in the increase in cross-sectional area (Fig.…”

Mechanisms of Cancer Cachexia

“…Expression of the mouse ether-a-go-go related gene (Mergla), a voltage-gated K ϩ channel, has been shown to be upregulated in skeletal muscle of mice undergoing atrophy as a result of both tumor implantation and disuse (270). Moreover, ectopic expression of Mergla in skeletal muscle induces proteolysis through the ubiquitin-proteasome pathway resulting in atrophy, while ectopic expression of a dysfunctional dominant negative mutant of Mergla, or treatment with astemizole, a Mergla channel blocker, inhibits atrophy and decreases proteolysis through the ubiquitin-proteasome pathway.…”

The Ubr2 gene is expressed in skeletal muscle atrophying as a result of hind limb suspension, but not Merg1a expression alone

“…This method results in gene transcription and translation in SKM in our laboratory. 22,23,25 Real Time PCR. Trizol reagent (Invitrogen; Carlsbad, CA) was used to extract total RNA from GMs according to manufacturer's instructions.…”

“…Sample CT values were normalized to (subtracted from) the CT values of the 18S "housekeeping" gene and the number 2 was raised to a power equal to the difference between the sample CT values of the 18S subunit and the gene of interest. 22,23,25 Study 1 Experimental Design. Three groups of five mice each were hindlimb suspended 22 for either 2, 4 or 7 days.…”

“…22,23,25 Study 1 Experimental Design. Three groups of five mice each were hindlimb suspended 22 for either 2, 4 or 7 days. A fourth group of five mice were allowed to remain weight bearing and were used as day 0 controls (n=20).…”