Transverse Tubule Morphology and Local Calcium Signaling in Skeletal Muscle Health and Disease

Abstract

Ca2+ sparks are spatially restricted elevations in myoplasmic Ca2+ that arise from the opening of a small number of clustered sarcoplasmic reticulum Ca2+ release channels (RyR). Ca2+ sparks are not readily detected in healthy intact adult skeletal muscle, but are observed in developing skeletal muscle and in stressed adult muscle fibers. Recent evidence bolsters a role for T-tubule/DHPR suppression of RyR activity in adult healthy fibers. Local destabilization of DHPR-RyR interactions may allow for RyR activation by agonists (i.e., myoplasmic Ca2+) which activate Ca2+ sparks. Using several models which produce spontaneous Ca2+ sparks (i.e., development, dedifferention and muscular dystrophy) we take a structure/function approach to gain further insights into the mechanisms by which Ca2+ sparks are activated and the role of T-tubules in regulating CICR in skeletal muscle health and disease. Using laser scanning confocal microscopy to monitor spontaneous Ca2+ sparks and T-tubule morphology we provide a detailed analysis of the spatial distribution of Ca2+ sparks with respect to the morphology of the T-tubule network. In addition, we assess whether sarcolemmal Ca2+ influx promotes the occurrence of Ca2+ sparks. Understanding the mechanisms that lead to activation of Ca2+ sparks in intact skeletal muscle will provide critical information into the regulation of RyR in both healthy and pathological conditions.