George G. Rodney, Ph.D.
Ph.D., Baylor College of Medicine, Houston
Postdoctoral, University of Maryland, Baltimore
Real-time imaging of sub-cellular reactive oxygen species, Ca2+ signaling, and excitation-contraction coupling in skeletal muscle under physiological and pathophysiological conditions.
The research in my lab revolves around the study of muscle physiology and function, with a focus on Ca2+ channels and redox signaling and how these processes are altered under conditions of stress, injury and pathology. Skeletal muscle contraction is activated through voltage dependent release of Ca2+ from the intracellular storage location, the sarcoplasmic reticulum (SR) through ryanodine receptors (RyR). Ca2+ release through RyR is regulated by endogenous proteins (e.g. calmodulin), Ca2+, and reactive oxygen species (ROS). ROS have long been associated with inflicting biological damage and have been implicated in the pathology of many conditions, including neoplastic, cardiovascular, respiratory, inflammatory and degenerative diseases, as well as aging, muscular dystrophy, and muscle fatigue. Over the last several decades there has been mounting evidence that low-to-moderate levels of ROS play important regulatory roles in cells. Due to their reactivity and intracellular spatial buffering ROS are likely to have relatively short diffusion distances, resulting in local microdomains containing high concentrations of reactive species. This would be analogous to microdomains of Ca2+ signaling such as Ca2+ sparks. Understanding the spatial and temporal production of ROS is thus a key element in signal transduction. We use a variety of techniques to assess sub-cellular ROS production (cytosolic, mitochondrial, and the endoplasmic/sarcoplasmic reticulum), excitation-contraction coupling, Ca2+ signaling, and in-vitro force measurements in skeletal muscle. These include confocal fluorescent imaging, fluorescent detection of ROS production, whole-cell patch clamping, immuno-fluorescence imaging, in-vivo electroporation of cDNA constructs, and use of cells from transegenic and gene knockout animals.
Clinical Implications: Site-specific ROS inhibitors as potential therapeutic targets. The identification of redox signaling pathways that contribute to muscle contractile dysfunction may provide potential new targets for the treatment and prevention of a variety of disorders that exhibit muscle weakness, ranging from myotonic and Duchenne dystrophies, chronic inflammatory diseases, cancer, type 2 diabetes, chronic heart failure, and aging. The potential clinical benefit for such targeted treatment is enormous