Although research has deepened our understanding of the role and functioning of HIFs, many questions remain unanswered today.
By Pierre-Luc Dubé
Hypoxia-induced factor (HIF) is found in every cell of the human body. It was discovered in 1992 by a researcher named Gregg Semanza. It was isolated for the first time in 1993, and its protein components were identified in 1995. Although research has deepened our understanding of the role and functioning of HIFs, many questions remain unanswered today. However, some hypotheses can be put forward regarding HIFs influence on physiological and pathological components of the muscle in a situation of hypoxia.
What is the HIF-1α factor?
HIF-1α factor is a protein complex stimulating and facilitating specific genes expression in the presence of a small oxygen concentration. It is composed of two sub-units: α and β. HIF-1α is constituted of 826 amino acids and represents 15 exons on chromosome 14q21-q24 of the human genotype. There are 3 types of HIF-α: HIF-1α, HIF-2α and HIF-3α. The factor is stabilized by the presence of reactive oxygen species, nitric oxide, and some oxidative system products and waste.
First, in the presence of a normal oxygen level, the protein prolyl hydroxylase (PHD) hydrolyzes HIF-1α (addition of an OH group) in order to increase its affinity for the Von Hippel-Lindau (VHL) gene, a protein responsible for suppressing tumors. Their combination makes it possible to identify HIF-1α for degradation through enzymatic complexes called proteasomes, which prevents transcription.
In hypoxia, the PHD and the inhibitor factor of HIF-1 (FIH) are inhibited, which allows the binding of HIF-1β and p300 / CBP to HIF-1α in order to activate the transcription of specific proteins by binding to the hypoxia response element (HRE) in the DNA molecule. The factor p300 / CBP is said to coordinate and interact with various signals responsible for protein transcription in order to modulate the expression of genes involved in a physiological response. Thus, by this cascade of events, the muscle is able to adapt to the lack of oxygen by activating the transcription of specific proteins responsible for the response and adaptations to hypoxia. When the oxygen concentration returns to normal, the factor is degraded to amino acids.
Roles of HIF-1α
HIF-1α is implicated in several physiological processes such as vascular system growth, red blood cells production, cell growth and aging, inflammatory reactions and the energy metabolism. Thus, this protein directly influences skeletal muscle.
In fact, HIF-1α is said to play an essential role in the regulation of anaerobic glycolysis. Mason et al. (2004) have shown that the absence of HIF-1α leads to a reduction in the concentration of lactate, in hypoxia, for the same level of cellular adenosine triphosphate (ATP). This implies that the contribution of the aerobic system is increased due to the absence of lactate from the accumulation of pyruvate, the end product of glycolysis. This phenomenon could be explained by an increase in the activity of enzymes found in the mitochondria and by a greater contribution of fatty acids. These adaptations would be used to compensate for the drop in energy intake (ATP) normally coming from glycolysis. In this sense, physical activity mimics a situation of local hypoxia, which reduces the level of oxygen and causes the accumulation of cellular HIF-1α. With the reduced oxygen level, HIFs would promote the enzymatic activity found in the anaerobic lactic pathway. In addition, factor HIF-1α would stimulate the production of erythropoietin (EPO) and increase the concentration of red blood cells.
HIF-1α is said to be responsible for phagocytic invasion in order to remove cellular debris following trauma, in addition to accelerating the growth and regeneration of skeletal muscle. For example, a broken tissue (physical activity, direct hit, etc.) would induce stress on the muscle favoring the accumulation of HIF-1α in the cell. Thus, the expression of specific genes responding to hypoxia would result in a higher level of macrophages at the site of the lesion. In addition, cell proliferation as well as a greater quantity of growth factors and proteins responsible for cell replication are noticed in the presence of trauma.
An increase in vascularization is observed following an infarction with selective inhibition of PHD, the protein responsible for keeping HIFs inactive in normal situations. Bao et al. (2010) also noted an increase in circulating hemoglobin (the cell responsible for transporting blood oxygen) and EPO. This same activation is also observed in the skeletal muscle and the kidney. In situations of hypoxia, De Theije et al. (2015) demonstrated an increase in the number of capillaries in type I fibers of the soleus muscle in mice.
Due to its wide involvement in the various systems affecting muscle structures, the HIF-1α protein could be used for performance purposes, but also for the treatment of certain medical conditions such as infarctions and cancers.
Following significant muscular effort, it is possible to witness the death of excessively damaged cells. Inhibition of factor HIF-1α would slow down the healing process. Indeed, the expression of cyclo-oxygenase-2 (COX-2) would be reduced. COX-2 is an enzyme involved in modulating the activation as well as the proliferation and migration of cells responsible for tissue regeneration. Thus, some athletes could apply this phenomenon to promote a faster return to play in the event of injury or to increase their training volume in order to improve their performance.
Bao et al. (2010) have also demonstrated that HIF-1α improves long-term function and ventricular vascularization following a cardiac incident such as a heart attack. This adaptation partially counterbalances the damage to the heart muscle, thus reducing its dysfunction.
Conversely, inactivation of HIFs could limit the proliferation of cancer cells, and therefore the severity of tumors. However, this last point must be studied and confirmed, considering that research is ambivalent on this subject at the moment.
HIF-1α is involved in several physiological functions affecting skeletal muscles during exercise and during recovery. However, despite numerous researches and discoveries, some mechanisms where HIF-1α seems to have an influence must be clarified. A deeper knowledge of the subject could give us a better indication of the potential uses of controlling this factor.
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