PGC-1α mediates a rapid, exercise-induced downregulation of glycogenolysis in rat skeletal muscle

Abstract

Key points: Long-term endurance exercise training results in a reduction in the rates of muscle glycogen depletion and lactic acid accumulation during submaximal exercise; this adaptation is mediated by an increase in muscle mitochondria. There is evidence suggesting that short-term training induces adaptations that downregulate glycogenolysis before there is an increase in functional mitochondria. We discovered that a single long bout of exercise induces decreases in expression of glycogenolytic and glycolytic enzymes in rat skeletal muscle; this adaptation results in slower rates of glycogenolysis and lactic acid accumulation in muscle during contractile activity. Two additional days of training amplified the adaptive response, which appears to be mediated by PGC-1α; this adaptation is biologically significant, because glycogen depletion and lactic acid accumulation are major causes of muscle fatigue.

Abstract: Endurance exercise training can increase the ability to perform prolonged strenuous exercise. The major adaptation responsible for this increase in endurance is an increase in muscle mitochondria. This adaptation occurs too slowly to provide a survival advantage when there is a sudden change in environment that necessitates prolonged exercise. In the present study, we discovered another, more rapid adaptation, a downregulation of expression of the glycogenolytic and glycolytic enzymes in muscle that mediates a slowing of muscle glycogen depletion and lactic acid accumulation. This adaptation, which appears to be mediated by PGC-1α, occurs in response to a single exercise bout and is further enhanced by two additional daily exercise bouts. It is biologically significant, because glycogen depletion and lactic acid accumulation are two of the major causes of muscle fatigue and exhaustion.

Figure 1. Effect of exercise on rat triceps muscle enzyme activity

One bout of exercise results in downregulation of expression of glycogen phosphorylase, phosphorylase kinase, phosphofructokinase (PFK), glyceraldehyde phosphate dehydrogenase (GAPDH) and total lactate dehydrogenase in rat triceps muscle. Two additional daily exercise bouts result in a further decrease in expression of these enzymes. Values are means ± SEM for 6 animals per group. *P < 0.01, exercise vs. sedentary; **P < 0.001, 3 days exercise vs. 1 day exercise and sedentary.

Figure 2. Effect of exercise on rat triceps muscle glycogen depletion and lactate accumulation

One bout of exercise results in a reduction in glycogen depletion and lactate accumulation in rat triceps muscle stimulated to contract in situ ∼18 h after exercise. Two additional daily exercise bouts enhance this adaptation. A, decreases in muscle glycogen. *P < 0.01, control muscle versus muscles stimulated to contract. B, rates of glycogenolysis. *P < 0.01, 1 day of training versus no training; **P < 0.001, 3 days training versus no training and 1 day of training. C, increases in muscle lactate concentration. *P < 0.01, 1 and 3 days training versus no training. D, rates of lactate accumulation. *P < 0.01, 1 day training versus no training; **P < 0.001, 3 days training versus no training and 1 day of training. Values are means ± SEM for 14 to 20 muscles per group.

Figure 3. Effect of exercise on skeletal muscle mitochondria

A, three daily bouts of exercise do not result in an increase in functional mitochondria in skeletal muscle as evidenced by no increase in the capacity for pyruvate oxidation. B, one bout of exercise results in an increase in PGC-1α expression measured ∼18 h after exercise. *P < 0.01, exercise versus sedentary. C, overexpression of PGC-1α in rat triceps muscle by means of electroporation resulted in downregulation of expression of phosphorylase, phosphorylase kinase and phosphofructokinase (PFK). D, knockdown of PGC-1α in C₂C₁₂ myotubes by transfection with PGC-1α shRNA results in increased expression of phosphorylase, phosphorylase kinase and phosphofructokinase. *P < 0.01, control versus empty vector (EV) or scrambled RNA (Scr). Values are means ± SEM for 6 rats per group.