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.

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

“…This parameter is highly dependent on calcium homeostasis (Berchtold, Brinkmeier, & Muntener, 2000). Interestingly, muscle PGC‐1α remodels sarcoplasmic reticulum calcium handling (Summermatter et al., 2012) and thereby possibly affects muscle contraction and ultimately locomotor function. Furthermore, neuromuscular junctions, which constitute the interface allowing a proper communication between motor neurons and muscles, are severely deteriorated during aging (Tintignac, Brenner, & Ruegg, 2015).…”

PGC-1α and exercise in the control of body weight

“…69 Furthermore, the activity of calcium-dependent signaling pathways via prolongation of myoplasmic calcium transients is increased by PGC-1a and similarly PGC-1a activates the transcription of nitric oxide synthase (inducible and endothelial, but not neuronal), which promotes elevated levels of nitric oxide. 35,70 By contrast, some other upstream activators, namely AMPK and p38 are not affected by ectopic expression of PGC-1a. 49,71 On the contrary, glycogen levels are elevated in response to PGC-1a and an inverse correlation between muscle glycogen content and AMPK activity has been established.…”

“…34 Indeed, overexpression of PGC1a shifts muscle appearance from a white to a reddish color, 34 promotes mitochondrial biogenesis of intramyofibrillar and subsarcolemmal mitochondria with concomitant reductions in myofibrillar volume, 35 alters MHC (myosin heavy chain) composition from MHC IIb and x towards more IIa and I, 34 switches metabolism from glycolytic to oxidative 34 and slows down calcium handling. 35 Consequently, endurance performance is improved, whereas maximal force generation is significantly reduced. 35 Inversely, PGC-1a muscle-specific knock-out animals exhibit a shift from oxidative type I and IIa towards type IIx and IIb muscle fibers, and a reduced oxidative capacity.…”

“…35 Consequently, endurance performance is improved, whereas maximal force generation is significantly reduced. 35 Inversely, PGC-1a muscle-specific knock-out animals exhibit a shift from oxidative type I and IIa towards type IIx and IIb muscle fibers, and a reduced oxidative capacity. 36,37 Thus, PGC-1a seems to drive fiber-type conversion in all its facets.…”

“…This is essentially based on the direct demonstration that sedentary mice with ectopic expression of PGC-1a have a higher endurance capacity when they are forced to run and their isolated muscles are resistant to fatigue. 34,35,57 Many additional effects of exercise, which are crucial for metabolic health, cannot simply be mimicked by the sole induction of PGC-1a. A trigger, such as exercise, is mandatory to increase energy expenditure and to initiate metabolic cycling.…”