Loss of Skeletal Muscle HIF-1α Results in Altered Exercise Endurance

Abstract

The physiological flux of oxygen is extreme in exercising skeletal muscle. Hypoxia is thus a critical parameter in muscle function, influencing production of ATP, utilization of energy-producing substrates, and manufacture of exhaustion-inducing metabolites. Glycolysis is the central source of anaerobic energy in animals, and this metabolic pathway is regulated under low-oxygen conditions by the transcription factor hypoxia-inducible factor 1α (HIF-1α). To determine the role of HIF-1α in regulating skeletal muscle function, we tissue-specifically deleted the gene encoding the factor in skeletal muscle. Significant exercise-induced changes in expression of genes are decreased or absent in the skeletal-muscle HIF-1α knockout mice (HIF-1α KOs); changes in activities of glycolytic enzymes are seen as well. There is an increase in activity of rate-limiting enzymes of the mitochondria in the muscles of HIF-1α KOs, indicating that the citric acid cycle and increased fatty acid oxidation may be compensating for decreased flow through the glycolytic pathway. This is corroborated by a finding of no significant decreases in muscle ATP, but significantly decreased amounts of lactate in the serum of exercising HIF-1α KOs. This metabolic shift away from glycolysis and toward oxidation has the consequence of increasing exercise times in the HIF-1α KOs. However, repeated exercise trials give rise to extensive muscle damage in HIF-1α KOs, ultimately resulting in greatly reduced exercise times relative to wild-type animals. The muscle damage seen is similar to that detected in humans in diseases caused by deficiencies in skeletal muscle glycogenolysis and glycolysis. Thus, these results demonstrate an important role for the HIF-1 pathway in the metabolic control of muscle function.

Immunohistochemical estimation of hypoxia in human obstructed bladder and correlation with clinical variables

“…Hence, when the bladder depletes the energy reserves during the voiding phase, detrusor contraction fails prematurely and the result is a PVR. Also, it is known that HIF-1α in hypoxic tissues regulates the expression of all enzymes in the glycolytic pathway [20][21][22][23][24]. These observations are consistent with the present study, where high expression of HIF-1α was four times more likely in men with UR.…”

“…In one of these studies, there was extensive muscle damage and reduced exercise time in genetically modified mice with loss of HIF-1α, relative to the wild-type mice, after prolonged exercise [24]. In a different study, an up-regulation of HIF-1α was a constant finding in athletes training in hypoxia, simultaneously with myoglobin synthesis, VEGF mRNA and glycolytic enzymes in muscle [25].…”

PGC-1α is coupled to HIF-1α-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells

“…HIF-1 ␣ protein levels also increase markedly in skeletal muscle in response to a single bout of exercise (45), and the effect of PGC-1␣ on HIF-1 that we describe here may prolong the activity of HIF-1 allowing for a sustained adaptive response to exercise. Finally, skeletal musclespecific HIF-1␣ knock out mice demonstrate that the increased expression of HIF target genes normally observed in response to exercise is HIF-1 dependent, suggesting a role for HIF in the adaptation of skeletal muscle in response to exercise (46). We propose that PGC-1␣ activation in skeletal muscle cells leads to increased oxygen consumption secondary to increased mitochondrial mass (Fig.…”

An initial blueprint for myogenic differentiation

“…It may also suggest that MRFs "delegate" tasks to "specialists." For example, by regulating the expression of Arnt, the dimerization partner of HIF1␣, MRFs may support an important role played by this transcription factor in the adaptive response of skeletal muscle to exercise-induced hypoxia and prevention of trauma (Mason et al 2004).…”