The long term goal of this project is to characterize factors involved in muscle regeneration, and use this knowledge to develop therapeutic treatments for impaired muscle regeneration, specifically that seen during aging. In mice and humans, advanced age is associated with a decline in skeletal muscle mass and strength, a process termed """"""""sarcopenia."""""""" A primary cause of this loss is the diminished ability of muscle-specific stem cells (called myoblasts) to divide and proliferate as needed to repair muscle damage. Many questions remain about which factors control myoblast proliferation, and especially which factors are affected by the aging process. Voltage gated calcium channel (Ca{v}) beta (Ca{v}B) subunits are classically known for their role in trafficking Cavs to the membrane and modulating their channel properties. Evidence also points to alternate functions for these proteins, which appear to enter the nucleus of many cell types, though no defined function has been established. This proposal provides evidence that the muscle specific Ca{v}B subunit, Ca{v}B1a, is expressed in proliferating myoblasts independently of Ca{v} expression;that Ca{v}B1a subunits translocate to the nucleus of myoblasts;and that knockdown of Ca{v}B1a expression level using RNA interference causes a significant reduction in myoblast proliferation. Thus Ca{v}B1a may be an important regulator of muscle regeneration via actions inside the nucleus, such as gene regulation. The specific experimental goals of this project are: 1) to define the mechanisms by which Ca{v}B1a translocates to the nucleus, which will be accomplished using a fractionation method to isolate yellow fluorescent protein (YFP) tagged Ca{v}B1a from purified nuclei, and utilize mass spectrometry based peptide sequencing to identify other proteins found in complex with Ca{v}B1a-YFP within the nucleus. 2) To identify genes involved in cell division which are differentially expressed in the absence of Ca{v}B1a (using an experimental knockdown model of Ca{v}B1a). And 3), to determine how Ca{v}B1a expression levels regulate myoblast proliferation and whether it can be a therapeutic target for impaired muscle regeneration during aging.
The age-related deterioration of skeletal muscle mass and performance is a leading cause of disability and morbidity in the elderly population worldwide, and represents a major health care cost. This project seeks to define factors which regulate skeletal muscle mass, and use these factors as therapeutics to prevent or reverse age-related decline in muscle mass. Thus, this project may contribute to a reduction in disability, mortality, and health care expenses.
| Taylor, Jackson; Pereyra, Andrea; Zhang, Tan et al. (2014) The Cav?1a subunit regulates gene expression and suppresses myogenin in muscle progenitor cells. J Cell Biol 205:829-46 |
