Adaptive Myogenesis under Hypoxia

Abstract

Previous studies have indicated that myoblasts can differentiate and repair muscle injury after an ischemic insult. However, it is unclear how hypoxia or glucose deprivation in the ischemic microenvironment affects myoblast differentiation. We have found that myogenesis can adapt to hypoxic conditions. This adaptive mechanism is accompanied by initial inhibition of the myoD, E2A, and myogenin genes followed by resumption of their expression in an oxygen-dependent manner. The regulation of myoD transcription by hypoxia is correlated with transient deacetylation of histones associated with the myoD promoter. It is noteworthy that, unlike the differentiation of other cell types such as preadipocytes or chondroblasts, the effect of hypoxia on myogenesis is independent of HIF-1, a ubiquitous regulator of transcription under hypoxia. While myogenesis can also adapt to glucose deprivation, the combination of severe hypoxia and glucose deprivation found in an ischemic environment results in pronounced loss of myoblasts. Our studies indicate that the ischemic muscle can be repaired via the adaptive differentiation of myogenic precursors, which depends on the levels of oxygen and glucose in the ischemic microenvironment.Skeletal muscle possesses the remarkable ability to withstand chronic ischemia. However, the newly developed muscle fibers tend to be smaller in diameter than those of healthy, nonischemic myofibers (46). Interestingly, chronic exposure to high altitude can also result in smaller myofiber area and lower muscle mass in mountaineers (25). Similar myofiber differences are also observed in healthy people who live at high altitude for generations (25). Taken together, these observations suggest that decreased oxygen tension or hypoxia alone may be sufficient to alter the differentiation of myoblasts.Ischemic muscle damage is repaired by myogenic satellite cells, a small population of precursor cells located between myofibers (12,23,47). When stimulated, the otherwise quiescent satellite cells undergo terminal differentiation into myocytes to regenerate damaged myofibers. It has been found that cultured satellite cells form new muscle fibers when transplanted into ischemic muscle (12). The myogenic differentiation of myoblasts is highly orchestrated by a family of myogenic regulatory factors (MRFs), such as myoD, myogenin, myf5, and MRF4 in collaboration with the E2A gene products (E12 or E47) and/or the myogenic enhancing factors (6, 41, 53). Although a plethora of information on the embryonic development of muscle exists, there is still a lack of clear understanding of how postnatal myogenic satellite cells are regulated during muscle regeneration, especially by their microenvironment.Tissue ischemia in myocardium and skeletal muscle results in hypoxia and elevates the expression of the hypoxia-inducible transcription factor HIF-1␣ and its downstream gene, VEGF (32,40). Although ischemic tissue is exposed to hypoxia and decreased nutritional supply, cells will alter their metabolism, proliferation, and differe...

Hyperbaric Oxygen Induces Basic Fibroblast Growth Factor and Hepatocyte Growth Factor Expression, and Enhances Blood Perfusion and Muscle Regeneration in Mouse Ischemic Hind Limbs

“…13 Regenerating muscle produces abundant angiogenic growth factors and induces angiogenesis. Myocyte regeneration occurs only under oxygen supply that is supported by blood perfusion through collaterals, 9 in agreement with our findings. HGF and bFGF potentially promote the growth of skeletal muscle.…”

“…[9][10][11][12] Acute ischemia induces gradual deterioration of energy metabolism in muscle, followed by cell death or adaptation. Proliferation of satellite cells begins as early as 3 days after the ischemic insult.…”

Differential Responses of Myogenic C2C12 Cells to Hypoxia between Growth and Muscle-Induction Phases: Growth, Differentiation and Motility

“…Ono et al demonstrated HIF-1α accumulated in the nucleus of myogenin-positive myoblasts on day 1 of differentiation, even at normal oxygen concentrations, while the amount of mRNA of the protein was constant 26) , corresponding to our present results. HIF-1α has an essential role in myogenic differentiation, and the regulation of protein expression is independent of oxygen concentration 25,26). HIF-1α protein expression was tightly regulated by HSP90 26) .…”

“…The effect of hypoxia on myogenesis is independent of HIF-1α, while myogenesis can also adapt to glucose deprivation 25) . Interestingly, HIF-1α protein is required for C2C12 myogenesis 26) .…”

“…Several studies have found that myogenesis can adapt to hypoxia. It is noteworthy that, unlike the differentiation of other cell types such as preadipocytes or chondroblasts, the effect of hypoxia on myogenesis is independent of HIF-1α, while myogenesis can also adapt to glucose deprivation 25) . Interestingly HIF-1α protein is required for C2C12 myogenesis 26) .…”