Effects of experimental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle

Abstract

Diabetes alters microvascular structure and function and is a major risk factor for cardiovascular diseases. In diabetic skeletal muscle, impaired angiogenesis and reduced VEGF-A expression have been observed, whereas in healthy muscle exercise is known to have opposite effects. We studied the effects of type 1 diabetes and combined exercise training on angiogenic mRNA expression and capillarization in mouse skeletal muscle. Microarray and real-time PCR analyses showed that diabetes altered the expression of several genes involved in angiogenesis. For example, levels of proangiogenic VEGF-A, VEGF-B, neuropilin-1, VEGFR-1, and VEGFR-2 were reduced and the levels of antiangiogenic thrombospondin-1 and retinoblastoma like-2 were increased. Exercise training alleviated some of these changes, but could not completely restore them. VEGF-A protein content was also reduced in diabetic muscles. In line with the reduced levels of VEGF-A and other angiogenic factors, and increased levels of angiogenesis inhibitors, capillary-to-muscle fiber ratio was lower in diabetic mice compared to healthy controls. Exercise training could not restore capillarization in diabetic mice. In conclusion, these data illustrate that type 1 diabetes is associated with reduced skeletal muscle capillarization and the dysregulation of complex angiogenesis pathways.

Voluntary Exercise Protects Heart from Oxidative Stress in Diabetic Rats

“…Many beneficial effects of exercise such as increasing insulin sensitivity, improved glucose uptake and alleviating diabet complications in diabetic animals and patients are reported. [4][5][6][7][8] Exercise is a modifiable behavioral factor which can produce several beneficial effects, including improved cardiac functions and diabetes complications. 9 Exercise training has been reported to increase SOD 10,11 and also partially reverses oxidative stress in the brains of ethanol-exposed rats.…”

One-year unsupervised individualized exercise training intervention enhances cardiorespiratory fitness but not muscle deoxygenation or glycemic control in adults with type 1 diabetes

“…Other human studies of cardiac adjustments to exercise training in type 1 diabetes are sparse. Vascular dysfunction is also evident in type 1 diabetes (Kindig et al 1998, Järvisalo et al 2004, Kivelä et al 2006, Mason et al 2006, probably having an independent limiting influence on muscle blood flow and therewith O 2 delivery also during exercise (Rissanen et al 2015). Aerobic training enhances endothelial function (Fuchsjäger-Mayrl et al 2002) and leads to muscle capillary neoformation (Wallberg-Henriksson et al 1982) in type 1 diabetes patients, and has also been shown to increase the expression of pro-angiogenic genes in type 1 diabetes mice (Kivelä et al 2006).…”

“…Vascular dysfunction is also evident in type 1 diabetes (Kindig et al 1998, Järvisalo et al 2004, Kivelä et al 2006, Mason et al 2006, probably having an independent limiting influence on muscle blood flow and therewith O 2 delivery also during exercise (Rissanen et al 2015). Aerobic training enhances endothelial function (Fuchsjäger-Mayrl et al 2002) and leads to muscle capillary neoformation (Wallberg-Henriksson et al 1982) in type 1 diabetes patients, and has also been shown to increase the expression of pro-angiogenic genes in type 1 diabetes mice (Kivelä et al 2006). However, animal (Kivelä et al 2006), cross-sectional (Mason et al 2006), and short-term training intervention (Wallberg-Henriksson et al 1984) studies have suggested that these vascular effects would be deficient relative to individuals without diabetes.…”

“…Aerobic training enhances endothelial function (Fuchsjäger-Mayrl et al 2002) and leads to muscle capillary neoformation (Wallberg-Henriksson et al 1982) in type 1 diabetes patients, and has also been shown to increase the expression of pro-angiogenic genes in type 1 diabetes mice (Kivelä et al 2006). However, animal (Kivelä et al 2006), cross-sectional (Mason et al 2006), and short-term training intervention (Wallberg-Henriksson et al 1984) studies have suggested that these vascular effects would be deficient relative to individuals without diabetes. Instead, subjects with and without type 1 diabetes have displayed a similar training-induced rise in enzymatic capacity to utilize O 2 (Wallberg-Henriksson et al 1984).…”

“…Based on cardiac impairments (Fang et al 2004, Gusso et al 2012, Rissanen et al 2015 and suggested deficient exercise effects on vasculature (Wallberg-Henriksson et al 1984, Kivelä et al 2006, Mason et al 2006 in type 1 diabetes, we hypothesized that training would overall elicit lesser improvements in V O 2peak , peak O 2 pulse, and active muscle deoxygenation in adults with type 1 diabetes than in well-matched adults with no diabetes. Furthermore, based on short-term training intervention studies (Chimen et al 2012), we expected to observe no training-induced reduction of HbA 1c in adults with type 1 diabetes.…”