The ERG1 K+ Channel Protein Is More Abundant in the Denervated Skeletal Muscle of Rodents

Abstract

Skeletal muscle atrophy is the loss of muscle mass and strength that occurs with normal aging, neural and muscle injuries, starvation and diseases such as diabetes, neuropathies, muscular dystrophy, cancer and sepsis cachexia, etc. The atrophy of skeletal muscle can be incapacitating and is related to increased disability, morbidity and mortality in people. We have shown that the ERG1a alternative splice variant of the ERG1 K+ channel is up‐regulated in the skeletal muscle of mice experiencing atrophy as a consequence of cancer cachexia and disuse (i.e., hind limb unweighting, a condition in which muscle action potentials are reduced). In fact, the ERG1 protein is up‐regulated after 4 days of hind limb unweighting, which is prior to a significant loss in muscle cross sectional area, strongly suggesting ERG1 is involved in the onset of muscle loss. Further, we have shown that the ERG1a channel contributes to protein breakdown in muscle by increasing both ubiquitin proteasome proteolysis (UPP) and intracellular calcium concentration with a subsequent increase in calpain activity. Because skeletal muscle atrophy occurs rapidly in denervated skeletal muscle, we hypothesized that ERG1 would also increase in denervated muscles. To test this hypothesis, we performed sciatic nerve transection on mice and rats and collected gastrocnemius and soleus muscles at 0, 4, 7 and 14 days after surgery. Decreased muscle weight and myofiber cross sectional area demonstrate that the muscles were successfully denervated and underwent atrophy. Immunoblot with anti‐ERG1 antibodies demonstrates that indeed the ERG1 protein increases post denervation in mice. Further, immunohistochemistry demonstrates that ERG1 protein also increases in denervated soleus of rats. Interestingly, confocal microscopy analysis of these tissues shows that the ERG1 protein is localized in the sarcolemma and t‐tubules of denervated rat skeletal muscle as it is in heart. The t‐tubule location places it in the vicinity of the calcium release apparatus where it can affect calcium release. We conclude that ERG1 protein is upregulated in the t‐tubules and sarcolemma of denervated muscle and, because it is up‐regulated in other atrophy models, ERG1 is a consistent marker of skeletal muscle atrophy.Support or Funding InformationThis research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number NIH NIAMS 1R03AR053706‐01A2 to ALP. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.