Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1α Pathway

Abstract

Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before the onset of the disease. It is well accepted that physical activity improves glycemic control, but the knowledge on underlying mechanisms mediating the beneficial effects remains incomplete. Exercise is accompanied by a decrease in intramuscular oxygen levels, resulting in induction of HIF-1α. HIF-1α is a master regulator of gene expression and might play an important role in skeletal muscle function and metabolism. Here we show that HIF-1α is important for glucose metabolism and insulin action in skeletal muscle. By using a genome-wide gene expression profiling approach, we identified and as two novel exercise/HIF-1α-regulated genes in skeletal muscle. Loss of Rab20 impairs insulin-stimulated glucose uptake in human and mouse skeletal muscle by blocking the translocation of GLUT4 to the cell surface. In addition, exercise/HIF-1α downregulates the expression of , a well-known negative regulator of insulin action. In conclusion, we are the first to demonstrate that HIF-1α is a key regulator of glucose metabolism in skeletal muscle by directly controlling the transcription of and These results hint toward a novel function of HIF-1α as a potential pharmacological target to improve skeletal muscle insulin sensitivity.

HIF-1α as a Mediator of Insulin Resistance, T2DM, and Its Complications: Potential Links With Obstructive Sleep Apnea

“…TXNIP has been found to enhance insulin secretion and glucagon-like peptide 1 (GLP-1) signaling via regulation of a microRNA (Alhawiti et al, 2017;Thielen and Shalev, 2018). Under conditions applied in the study of Görgens et al (2017) simulating physical exertion and hypoxia, RAB20 upregulation and TXNIP downregulation mediated by HIF-1α were detected in the investigated tissues, which may explain the beneficial influence in this case. These results suggest that HIF-1α stabilization in the combined setting of muscle contraction and hypoxia can counteract the development of IR (Görgens et al, 2017).…”

“…Although many studies support the thesis that hypoxia accompanied by HIF-1α overexpression is harmful to metabolism, there are also reports that suggest the beneficial influence of HIF-1α stabilization on glucose and lipid metabolism (Mackenzie et al, 2012;Jun et al, 2013;Mesarwi et al, 2015;Thomas et al, 2017). The study of Görgens et al (2017) on human skeletal muscle cells reports that hypoxia in combination with muscle activity improved glucose metabolism and insulin activity via the HIF-1α and its influence on RAB20 and TXNIP transcription. Rab20 is a member of the Rab family of proteins, regulating intracellular trafficking and vesicle formation (Hackenbeck et al, 2011).…”

Oxygenation of adipose tissue: A human perspective

“…Therefore, hypoxia exposure during exercise might have additive or synergistic effects on peripheral glucose uptake. Indeed, exposing human myotubes to 7% O 2 in combination with electrical pulse stimulation (EPS), to mimic exercise, increased glucose uptake to a higher extent than EPS under 21% O 2 , which seems at least partly because of an insulin‐sensitizing effect of hypoxia . Taken together, hypoxia exposure may improve glucose homeostasis via insulin‐dependent and insulin‐independent effects, but more studies in humans on putative underlying mechanisms are needed.…”

In vitro experimental models for examining the skeletal muscle cell biology of exercise: the possibilities, challenges and future developments

“…[16]), AICAR [60,91], caffeine [89][90][91] and PFI [22-25, 65, 118] applied through daily pulses interspersed by periods of 'rest'. Overall, a combination of these exercise-like treatments with other techniques, such as hypoxic cell culture conditions (which has recently been combined with EPS [39]), mechanical stretching, co-culturing with other cell types and perifusion systems, could make each model more representative of in vivo exercise physiology. Fig.…”