Plasticity of the Muscle Proteome to Exercise at Altitude

Abstract

The ascent of humans to the summits of the highest peaks on Earth initiated a spurt of explorations into the physiological consequences of physical activity at altitude. The past three decades have demonstrated that the resetting of respiratory and cardiovascular control with chronic exposure to altitudes above 4000 m is accompanied by important structural-functional adjustments of skeletal muscle. The fully altitude-adapted phenotype preserves energy charge at reduced aerobic capacity through the promotion of anaerobic substrate flux and tighter metabolic control, often at the expense of muscle mass. In seeming contrast, intense physical activity at moderate hypoxia (2500 to 4000 m) modifies this response in both low and high altitude natives through metabolic compensation by elevating local aerobic capacity and possibly preventing muscle fiber atrophy. The combined use of classical morphometry and contemporary proteomic technology provides a highly resolved picture of the temporal control of hypoxiainduced muscular adaptations. The muscle proteome signature identifies mitochondrial autophagy and protein degradation as prime adaptive mechanisms to passive altitude exposure and ascent to extreme altitude. Protein measures also explain the lactate paradox by a sparing of glycolytic enzymes from general muscle wasting. Enhanced mitochondrial and angiogenic protein expression in human muscle with exercise up to 4000 m is related to the reduction in intramuscular oxygen content below 1% (8 torr), when the master regulator of hypoxia-dependent gene expression, HIF-1alpha, is stabilized. Accordingly, it is proposed here that the catabolic consequences of chronic hypoxia exposure reflect the insufficient activation of hypoxia-sensitive signaling and the suppression of energy-consuming protein translation. The ascent of humans to the summits of the highest peaks on Earth initiated a spurt of explorations into the physiological consequences of physical activity at altitude. The past three decades have demonstrated that the resetting of respiratory and cardiovascular control with chronic exposure to altitudes above 4000 m is accompanied by important structural-functional adjustments of skeletal muscle. The fully altitude-adapted phenotype preserves energy charge at reduced aerobic capacity through the promotion of anaerobic substrate flux and tighter metabolic control, often at the expense of muscle mass. In seeming contrast, intense physical activity at moderate hypoxia (2500 to 4000 m) modifies this response in both low and high altitude natives through metabolic compensation by elevating local aerobic capacity and possibly preventing muscle fiber atrophy. The combined use of classical morphometry and contemporary proteomic technology provides a highly resolved picture of the temporal control of hypoxia-induced muscular adaptations. The muscle proteome signature identifies mitochondrial autophagy and protein degradation as prime adaptive mechanisms to passive altitude exposure and ascent to extreme altitude. P...

Effects of acid–base balance and high or low intensity exercise on VEGF and bFGF

“…However, it was shown that VEGF levels in muscle interstitium increased 3 and 8 h post a high-volume endurance exercise (Flueck 2009;Hoier et al 2010). The authors concluded that exercise causes a secretion of VEGF from human skeletal muscle cells.…”

Gene-Pharmacologial Effects on Exercise-Induced Muscle Gene Expression in Healthy Men

“…The expression of HIF-1α and COX4I2 transcripts and HIF-1α protein is thought to represent markers of tissue hypoxia [22]. We reported before that their expression in vastus lateralis muscle after endurance type bicycle exercise is markedly affected by ambient hypoxia [16], which is known to produce a further lowering of tissue oxygenation [17]. This finding compares to a higher gene expression for components of mitochondrial respiration and Krebs cycle with the lowering of levels in metabolically active yeast [23].…”

“…We therefore wished to assess the interaction of genetical and pharmacological inhibition of ACE on muscle transcript expression post-exercise. We specifically hypothesized that hypoxia-sensitive transcript expression of isoform 1 and 2 of subunit 4 of cytochrome c oxidase, COX4I1 and COX4I2, and HIF-1α transcript and protein [14][15][16], would show ACE-dependent level alterations in knee extensor muscle during recovery from cycle-type endurance exercise as this lowers muscle oxygenation in relation to capillary perfusion [17].…”

Hypoxia and muscle maintenance regulation

“…The adaptations of muscle in humans exposed to high altitude have been extensively studied and the overall consensus is that muscle adapts to high altitude hypoxia by a decrease in oxidative capacity, whereas combined with exercise training, muscle OXPHEN may even improve [6,33,34]. In addition, numerous experiments have been conducted in which rodents were exposed to chronic hypoxia and in some of these studies, a relative loss of muscle OXPHEN was indeed found, but not in others.…”