Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type

Summermatter S, Thurnheer R, Santos G, Mosca B, Baum O, Treves S, Hoppeler H, Zorzato F, Handschin C. Remodeling of calcium handling in skeletal muscle through PGC-1 alpha: impact on force, fatigability, and fiber type. Am J Physiol Cell Physiol 302: C88-C99, 2012. First published September 14, 2011; doi:10.1152/ajpcell.00190.2011.-Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha). PGC-1 alpha promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1 alpha in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1 alpha, we now investigated the effect of PGC-1 alpha on calcium handling in skeletal muscle. We demonstrate that PGC-1 alpha induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1 alpha overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1 alpha. Our results reveal a novel role of PGC-1 alpha in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1 alpha to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1 alpha reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.