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

Author:

Görgens Sven W.1,Benninghoff Tim2,Eckardt Kristin13,Springer Christian2,Chadt Alexandra2ORCID,Melior Anita1,Wefers Jakob1,Cramer Andrea1,Jensen Jørgen4,Birkeland Kåre I.5,Drevon Christian A.3,Al-Hasani Hadi26,Eckel Jürgen16ORCID

Affiliation:

1. Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center (DDZ), Düsseldorf, Germany

2. Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), Düsseldorf, Germany

3. Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

4. Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway

5. Department of Endocrinology, Morbid Obesity, and Preventive Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway

6. German Center for Diabetes Research (DZD e.V.), Düsseldorf, Germany

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 RAB20 and TXNIP 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 TXNIP, 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 RAB20 and TXNIP. These results hint toward a novel function of HIF-1α as a potential pharmacological target to improve skeletal muscle insulin sensitivity.

Funder

Ministry of Science and Research of the State of North Rhine-Westphalia

Deutsche Forschungsgemeinschaft

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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