title: Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type.
abstract: Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α 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-1α 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-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α 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-1α 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.
authors.affiliation: Biozentrum, Department of Pharmacology/Neurobiology, University of Basel, Basel, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Summermatter
authors.forename: Raphael
authors.initials: R
authors.lastname: Thurnheer
authors.forename: Gesa
authors.initials: G
authors.lastname: Santos
authors.forename: Barbara
authors.initials: B
authors.lastname: Mosca
authors.forename: Oliver
authors.initials: O
authors.lastname: Baum
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
authors.forename: Hans
authors.initials: H
authors.lastname: Hoppeler
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000502:physiology*; D018763:Muscle Fatigue / Q000502:physiology*; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology*; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011897:Random Allocation; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D002118:Calcium