Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling

Radiation exposure accelerates the onset of age-related diseases such as diabetes, cardiovascular disease, and neoplasia and thus lends insight into in vivo mechanisms common to these disorders. Fibrosis and extracellular matrix (ECM) remodeling, which occur with aging, overnutrition, and following irradiation, are both risk factors for type-2 diabetes mellitus (T2DM) development. Our prior work demonstrated that monkeys with whole-body radiation exposure five to nine years prior had an increased incidence of skeletal muscle insulin resistance and T2DM. We hypothesized that irradiation-induced fibrosis alters muscle architecture predisposing irradiated animals to insulin resistance and overt diabetes. Rhesus macaques (Macaca mulatta; n=7-8/group) grouped as non-irradiated age-matched controls (NonRad-CTL), irradiated non-diabetic monkeys (Rad-CTL) and irradiated monkeys that subsequently developed diabetes (Rad-DM) were compared. Prior radiation exposure resulted in persistent skeletal muscle ECM changes including a relative overabundance of collagen IV and a trend of increased transforming growth factor beta 1 (TGFβ1). Notably, preservation of microvascular markers differentiated the irradiated diabetic and non-diabetic groups. Rad-DM had lower microvascular density, plasma nitrate, and heat shock protein 90 levels compared to Rad-CTL. These results are consistent with a protective effect of abundant microvasculature in maintaining glycemic control within radiation-induced fibrotic muscle.

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