Calcium Signaling in Skeletal Muscle Atrophy: A Novel Role for the ERG1alpha K+ Channel
Abstract
Skeletal muscle atrophy is a decline in muscle size and strength that can escalate morbidity and mortality in injured and ill people. It ensues rapidly with muscle disuse and complicates the healing and recovery process, interfering with an affected individual’s ability to work and perform necessary duties. This situation is especially impactful to military personnel, each of whom has great responsibility to perform critical and unique tasks. In addition to combat injuries, it has been estimated that “on base” injuries are occurring at a high level, resulting in Soldier down time; thus, there is a need to prevent muscle atrophy in these people so that they can recover more quickly. Indeed, muscle atrophy has a large negative impact on the human population in general, affecting injured and ill civilians as well as being a natural occurrence with aging. At present, the most effective therapy for skeletal muscle atrophy is exercise combined with a nutritious diet. Unfortunately, however, many people suffering with atrophy are unable to exercise sufficiently because of limitations imposed by the injury or illness, and the current pharmacological agents available to treat muscle atrophy are not adequately effective. Therefore, research designed to explore the mechanisms involved in the onset and perpetuation of this condition is critical to the development of improved therapies. We have novel preliminary data showing that increases of the HERG1 protein in skeletal muscle cells leads to an imbalance in the normal levels of cellular calcium, an important cellular “messenger” that controls many cell functions. Small changes in calcium concentration within specific locations of a cell can have devastating effects on the cell, even killing it. The mechanism(s) by which the HERG1 protein affects calcium levels in skeletal muscle cells is not known. Here we propose to investigate this mechanism and determine how HERG1 contributes to protein breakdown in skeletal muscle. Specifically, we will work with cells that contain HERG1 and those that do not, and we will measure the calcium levels in both sets of cells treated with and without various compounds designed to help us understand how HERG1 causes the calcium levels to increase and which mechanisms of degradation are affected. We suspect that the HERG1-mediated increase in calcium enhances activity of the protein degrading enzymes called calpains and that it also affects the types of skeletal muscle genes that are turned on and off, specifically those related to growth and protein breakdown. Thus, we suggest that HERG1 coordinates cellular systems contributing to skeletal muscle loss. The work is innovative because the role that HERG1 plays in skeletal muscle is not known nor has a role for it in calcium regulation within skeletal muscle been reported. Indeed, the majority of work done with HERG1A is within the realm of cardiac impulse physiology. This basic research is significant because it will produce information that will lead to identification of novel targets for muscle atrophy therapy and, thus development of more effective therapies for this debilitating condition.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810052
Entities
People
- Amber L Pond
Organizations
- Southern Illinois University
- United States Army