With increased skeletal muscle activity, there is a transition to a greater proportion of slow fibers while both metabolic capacity and reliance on fatty acid oxidation (FAO) are increased. Regulatory mechanisms for this adaptation remain poorly understood. We propose that the phosphatase calcineurin (Cn) may play a role in this process. Cn is activated by prolonged increases in intracellular calcium concentration, as seen with muscular activity. Further, cyclosporin A (CsA), a specific inhibitor of Cn activity, inhibits fiber type adaptations to increased activity. FAO enzymes are known to be regulated, by the peroxisome proliferator activated receptor alpha (PPARalpha). Activation is enhanced in the presence of PGC- 1, a PPARalpha co-activator. PGC-1 also controls mitochondrial number and functional capacity. The objectives of this project are i) to characterize the role of calcineurin in the regulation of mitochondrial FAO enzyme gene expression, ii) to characterize the roles of PPARalpha and PGC- 1 in the calcineurin-mediated activation of FAO enzymes, and iii) to examine the role of calcineurin and the PPARalpha/PGC-1 regulatory pathway in determining the skeletal muscle metabolic phenotype in vivo following exercise in normal and genetically engineered mice with altered PPARalpha or Cn function.
| Schaeffer, Paul J; Desantiago, Jaime; Yang, John et al. (2009) Impaired contractile function and calcium handling in hearts of cardiac-specific calcineurin b1-deficient mice. Am J Physiol Heart Circ Physiol 297:H1263-73 |
| Schaeffer, Paul J; Wende, Adam R; Magee, Carolyn J et al. (2004) Calcineurin and calcium/calmodulin-dependent protein kinase activate distinct metabolic gene regulatory programs in cardiac muscle. J Biol Chem 279:39593-603 |
