Hyperglycaemia correlates with skeletal muscle capillary regression and is associated with alterations in the murine double minute-2/forkhead box O1/thrombospondin-1 pathway in type 1 diabetic BioBreeding rats

• Published in: Diabetes & vascular disease research 2019-01, Vol.16 (1), p.28-37
• Main Authors: Aiken, Julian, Mandel, Erin R, Riddell, Michael C, Birot, Olivier
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - blood; Blood Glucose - metabolism; Capillaries - metabolism; Capillaries - pathology; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - pathology; Diabetic Angiopathies - blood; Diabetic Angiopathies - genetics; Diabetic Angiopathies - pathology; Disease Models, Animal; Muscle, Skeletal - blood supply; Nerve Tissue Proteins - metabolism; Proto-Oncogene Proteins c-mdm2 - metabolism; Rats, Inbred BB; Rats, Inbred Strains; Signal Transduction; Thrombospondin 1 - metabolism; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 1479-1641; 1752-8984
• DOI: 10.1177/1479164118805928

Type 1 diabetes can have deleterious effects on skeletal muscle and its microvasculature. Our laboratory has recently identified murine double minute-2 as a master regulator of muscle microvasculature by controlling expression levels of two key molecular actors of the angio-adaptive process: the pro-angiogenic vascular endothelial growth factor-A and the anti-angiogenic thrombospondin-1. Here, we show for the first time that in the soleus and plantaris muscles of the diabetes-prone BioBreeding rats, a rodent model of autoimmune type 1 diabetes, murine double minute-2 protein levels are significantly decreased, coinciding with elevated protein levels of thrombospondin-1 and its transcription factor forkhead box O1. Significant capillary regression was observed to similar extent in soleus and plantaris muscles of type 1 diabetic rats. Elevated blood glucose levels were correlated with the loss of capillaries, the reduction in murine double minute-2 expression and with the elevations in thrombospondin-1. Vascular endothelial growth factor-A protein levels were unaltered or even increased in diabetic animals, yet type 1 diabetic animals had less vascular endothelial growth factor receptor-2 abundance. The vascular endothelial growth factor-A/thrombospondin-1 ratio, a good indicator of skeletal muscle angio-adaptive environment, was decreased in type 1 diabetic muscle. Our results suggest that the murine double minute-2–forkhead box O1–thrombospondin-1 pathway plays an important role in angio-regulation of the skeletal muscle in the pathophysiological context of type 1 diabetes.