Energy metabolism in hypoxia: reinterpreting some features of muscle physiology on molecular grounds.

An holistic approach for interpreting classical data on the adaptation of the animal and, particularly, of the human body to hypoxic stress was promoted by the discovery of HIF-1, the "master regulator" of cell hypoxic signaling. Mitochondrial production of ROS stabilizes the O(2)-regulated HIF-1α subunit of the HIF-1 dimer promoting transaction functions in a large number of potential target genes, activating transcription of sequences into RNA and, eventually, protein production. The aim of the present preliminary study is to assess whether adaptive changes in oxygen sensing and metabolic signaling, particularly in the control of energy turnover known to occur in cultured cells exposed to hypoxia, are detectable also in the muscles of animals and man. For the present analysis, data obtained from the proteome of the rat gastrocnemius and of the vastus lateralis muscle of humans together with functional measurements were compared with homologous data from hypoxic cultured cells. In particular, the following variables were assessed: (1) the role of stress response proteins in the maintenance of ROS homeostasis, (2) the activity of the PDK1 gene on the shunting of pyruvate away from the TCA cycle in rodents and in humans, (3) the COX-4/COX-2 ratio in hypoxic rodents, (4) the overall efficiency of oxidative phosphorylation in humans during exercise in hypoxia, (5) some features of muscle mitochondrial autophagy in humans undergoing subchronic and chronic altitude exposure. Despite the limited number of observations and the differences in the experimental approach, some initial interesting results were obtained encouraging to pursue this innovative effort.