Stimulation of skeletal muscle angiogenesis in aged rats by (+)-epicatechin: Identification of underlying mechanisms

Abstract

Studies have linked the development of sarcopenia to reductions in capillary vessel network density and suggest that such changes may partly account for the loss of skeletal muscle (SkM) mass and function. Thus, the interest in identifying and evaluating safe and effective candidate compounds that can stimulate angiogenesis. We previously reported on the capacity of (+)-epicatechin (+Epi) to reverse SkM atrophy and loss of function in aged rats. We also reported on the apparent angiogenic effect of +Epi in mouse brain cortex. However, no studies have evaluated the angiogenic potential of +Epi in SkM. Using 23 month old male rats, we evaluated the angiogenic effect of 8 weeks of 1 mg/kg/day oral treatment of +Epi on SkM (gastrocnemius). To identify underlying mechanisms, we evaluated the PI3K/eNOS pathway, as well as the expression of the angiogenic factors HIF1-α, VEGF and VEGFR2. Results demonstrate that + Epi stimulates increases in protein levels for HIF1-α (∼35%), VEGF (∼40%), VEGFR2 (∼25%), as well as CD31 (capillaries, ∼25%). Such effects were linked with the activation (phosphorylation) of PI3K (∼30%), eNOS (∼90%), VEGFR2 at T951 (∼90%) and T996 amino acid sites (∼110%). +Epi also stimulated increased synthesis of phosphatidylinositol trisphosphate (∼30%) and tetrahydrobiopterine (∼90%), as well as of nitric oxide (∼140% in gastrocnemius and ∼70% in plasma) and cyclic guanosine monophosphate (∼90%) in gastrocnemius and in plasma (∼40%). In summary, in aged rats oral treatment with +Epi stimulates SkM angiogenesis and such actions may partly account for the reversal of the deleterious effects of sarcopenia.