Hypoxia inducible factor 1α links fast-patterned muscle activity and fast muscle phenotype in rats

Non-technical summary  Muscle fibres change when they are used differently, such as by exercise. Genetic studies have shown that a hyperactive form of the gene regulatory protein hypoxia inducible factor 1α (HIF-1α) occurs twice as often among strength-trained athletes as in the normal population. HIF-1α is ‘sensing’ the oxygen levels in cells, and the oxygen levels change by an order of magnitude in working muscle. We show that an ‘endurance’ type of activity reduces the level of HIF-1α, while short intense bursts of activity increases it. When HIF-1α was produced in higher quantities by introducing artificial genes in the muscle fibres they became larger and faster, and with a less oxidative metabolism. Thus, oxygen itself could be a trigger for changes in muscle. The composition of muscle fibres is strongly correlated to major lifestyle conditions such as diabetes and chronic obstructive pulmonary disease, and HIF-1α might provide a new molecular link.

Abstract  Exercise influences muscle phenotype by the specific pattern of action potentials delivered to the muscle, triggering intracellular signalling pathways. can be reduced by an order of magnitude in working muscle. In humans, carriers of a hyperactive polymorphism of the transcription factor hypoxia inducible factor 1α (HIF-1α) have 50% more fast fibres, and this polymorphism is prevalent among strength athletes. We have investigated the putative role of HIF-1α in mediating activity changes in muscle. When rat muscles were stimulated with short high frequency bursts of action potentials known to induce a fast muscle phenotype, HIF-1α increased by about 80%. In contrast, a pattern consisting of long low frequency trains known to make fast muscles slow reduced the HIF-1α level of the fast extensor digitorum longus (EDL) muscle by 44%. Nuclear protein extracts from normal EDL contained 2.3-fold more HIF-1α and 4-fold more HIF-1β than the slow soleus muscle, while von-Hippel-Lindau protein was 4.8-fold higher in slow muscles. mRNA displayed a reciprocal pattern; thus FIH-1 mRNA was almost 2-fold higher in fast muscle, while the HIF-1α level was half, and consequently protein/mRNA ratio for HIF-1α was more than 4-fold higher in the fast muscle, suggesting that HIF-1α is strongly suppressed post-transcriptionally in slow muscles. When HIF-1α was overexpressed for 14 days after somatic gene transfer in adult rats, a slow-to-fast transformation was observed, encompassing an increase in fibre cross sectional area, oxidative enzyme activity and myosin heavy chain. The latter was shown to be regulated at the mRNA level in C2C12 myotubes.