A drop in cellular oxygenation triggers tissue specific compensatory reactions aimed at preserving energy charge with the reduction in aerobic ATP production. The integrative nature of this response is pointed out by the resetting of respiratory and cardiovascular control and the promotion of anaerobic substrate flux and catabolism in skeletal muscle with chronic exposure of human subjects to extreme altitudes above 4000m sea level (Flueck 2009). In seeming contrast, intense physical activity in moderate hypoxia, i.e. altitudes of 2500 to 4000m above sea level, modifies this response in the untrained by elevating local aerobic capacity and possibly preventing muscle fibre atrophy (). The frequent lowering of muscle oxygen with physical work indicates that local hypoxia is an important signal for muscle plasticity. We have addressed this contention by studying adjustments of the muscle trait of aerobic power output with a multi-level approach. Transcript profiling in heterozygous deficient mice for hypoxia inducible factor 1 alpha (HIF-1A) identified broadly positive transcript control of gene ontologies involved in glycolysis, mitochondria respiration and capillary neo-formation by HIF-1A in severe hypoxia (10.5% O2); Däpp et al 2006). By contrast, expression control of lipid metabolism was inhibited in a HIF-1A dependent manner. Measures of selected gene messages in exercised human supported the implication of HIF-1A in hypoxia signalling towards the genome response in the first 24 hours of recovery and exposed that the outcome of hypoxia signalling is importantly modified by muscle differentiation. This was indicated by a delay in exercise induced up-regulation of HIF-1A dependent transcripts in untrained subjects by exercise in a hypoxic environment (12% O2; Schmutz et al 2010). By contrast, a specific promotion of mitochondrial, angiogenic and glycolytic transcripts was evident after endurance training under the co-stimulus of hypoxia compared to normoxic exercise. The reciprocal control of muscle gene expression in hypoxia trained and untrained state corresponded to changes in arterial oxygen saturation during exercise and related to a selectively elevated subsarcolemmal mitochondrial density and capillary-to-fibre ratio in locomoter muscle and increased aerobic performance in a hypoxic environment. The results support the view that hypoxia signalling in muscle towards gene regulation is aimed at preserving energy supply and is a function of the severity of hypoxic stress and modified by the makeup in the pathway of respiration.