HIF-1α Negatively Regulates Irisin Expression Which Involves in Muscle Atrophy Induced by Hypoxia

Exposure to high altitude environment leads to skeletal muscle atrophy. As a hormone secreted by skeletal muscles after exercise, irisin contributes to promoting muscle regeneration and ameliorating skeletal muscle atrophy, but its role in hypoxia-induced skeletal muscle atrophy is still unclear. Our results showed that 4 w of hypoxia exposure significantly reduced body weight and gastrocnemius muscle mass of mice, as well as grip strength and the duration time of treadmill exercise. Hypoxic treatment increased HIF-1α expression and decreased both the circulation level of irisin and its precursor protein FNDC5 expression in skeletal muscle. In in vitro, CoCl2-induced chemical hypoxia and 1% O2 ambient hypoxia both reduced FNDC5, along with the increase in HIF-1α. Moreover, the decline in the area and diameter of myotubes caused by hypoxia were rescued by inhibiting HIF-1α via YC-1. Collectively, our research indicated that FNDC5/irisin was negatively regulated by HIF-1α and could participate in the regulation of muscle atrophy caused by hypoxia.

HIF-1α Negatively Regulates Irisin Expression Which Involves in Muscle Atrophy Induced by Hypoxia

Background: Exposure to high altitude environment leads to skeletal muscle atrophy. As a hormone secreted by skeletal muscles after exercise, irisin contributes to promoting muscle regeneration and ameliorating skeletal muscle atrophy, but its role in hypoxia-induced skeletal muscle atrophy is still unclear. Methods & Results: Our results showed that 4 w of hypoxia exposure significantly reduced body weight and gastrocnemius muscle mass of mice, as well as grip strength and the duration time of treadmill exercise. Hypoxia treatment increased HIF-1α expression and decreased both the circulation level of irisin and its precursor protein FNDC5 expression in skeletal muscle. In vitro, CoCl2-induced chemical hypoxia and 1% O2 ambient hypoxia both reduced FNDC5, along with the increase of HIF-1α. Moreover, the decline of area and diameter of myotubes caused by hypoxia were rescued by inhibiting HIF-1α via YC-1. and Conclusions: Collectively, our research indicated that FNDC5/irisin was negatively regulated by HIF-1α and could participate in the regulation of muscle atrophy caused by hypoxia.

Altitude, Exercise, and Skeletal Muscle Angio-Adaptive Responses to Hypoxia: A Complex Story

Hypoxia, defined as a reduced oxygen availability, can be observed in many tissues in response to various physiological and pathological conditions. As a hallmark of the altitude environment, ambient hypoxia results from a drop in the oxygen pressure in the atmosphere with elevation. A hypoxic stress can also occur at the cellular level when the oxygen supply through the local microcirculation cannot match the cells’ metabolic needs. This has been suggested in contracting skeletal myofibers during physical exercise. Regardless of its origin, ambient or exercise-induced, muscle hypoxia triggers complex angio-adaptive responses in the skeletal muscle tissue. These can result in the expression of a plethora of angio-adaptive molecules, ultimately leading to the growth, stabilization, or regression of muscle capillaries. This remarkable plasticity of the capillary network is referred to as angio-adaptation. It can alter the capillary-to-myofiber interface, which represent an important determinant of skeletal muscle function. These angio-adaptive molecules can also be released in the circulation as myokines to act on distant tissues. This review addresses the respective and combined potency of ambient hypoxia and exercise to generate a cellular hypoxic stress in skeletal muscle. The major skeletal muscle angio-adaptive responses to hypoxia so far described in this context will be discussed, including existing controversies in the field. Finally, this review will highlight the molecular complexity of the skeletal muscle angio-adaptive response to hypoxia and identify current gaps of knowledges in this field of exercise and environmental physiology.

HIF-1–dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak

Extracellular adenosine has been implicated in vascular adaptation to hypoxia. Based on the observation that increases in intracellular adenosine can effectively elevate extracellular adenosine, we studied the contribution of adenosine kinase (AK, intracellular conversion of adenosine to adenosine monophosphate [AMP]) to vascular adenosine responses. Initial in vitro studies of ambient hypoxia revealed prominent repression of endothelial AK transcript (85% ± 2% reduction), protein, and function. Transcription factor binding assays and hypoxia inducible factor 1-α (HIF-1α) loss- and gain-of-function studies suggested a role for HIF-1α in transcriptional repression of AK. Moreover, repression of AK by ambient hypoxia was abolished in conditional HIF-1α mutant mice in vivo. Studies of endothelial barrier function revealed that inhibition or siRNA repression of AK is associated with enhanced adenosine-dependent barrier responses in vitro. Moreover, in vivo studies of vascular barrier function demonstrated that AK inhibition with 5′-iodotubericidin (1 mg/kg prior to hypoxia) significantly attenuated hypoxia-induced vascular leakage in multiple organs and reduced hypoxia-associated increases in lung water. Taken together, our data reveal a critical role of AK in modulating vascular adenosine responses and suggest pharmacologic inhibitors of AK in the treatment of conditions associated with hypoxia-induced vascular leakage (eg, sepsis or acute lung injury).