Differential vulnerability of skeletal muscle feed arteries to dysfunction in insulin resistance: impact of fiber type and daily activity

Abstract

Functional and structural heterogeneity exists among skeletal muscle vascular beds related, in part, to muscle fiber type composition. This study was designed to delineate whether the vulnerability to vascular dysfunction in insulin resistance is uniformly distributed among skeletal muscle vasculatures and whether physical activity modifies this vulnerability. Obese, hyperphagic Otsuka Long-Evans Tokushima fatty rats (20 wk old) were sedentary (OSED) or physically active (OPA; access to running wheels) and compared with age-matched sedentary Long-Evans Tokushima Otsuka (LSED) rats. Vascular responses were determined in isolated, pressurized feed arteries from fast-twitch gastrocnemius (GFAs) and slow-twitch soleus (SFAs) muscles. OSED animals were obese, insulin resistant, and hypertriglyceridemic, traits absent in LSED and OPA rats. GFAs from OSED animals exhibited depressed dilation to ACh, but not sodium nitroprusside, and enhanced vasoconstriction to endothelin-1 (ET-1), but not phenylephrine, compared with those in LSED. Immunoblot analysis suggests reduced endothelial nitric oxide synthase phosphorylation at Ser1177 and endothelin subtype A receptor expression in OSED GFAs. Physical activity prevented reduced nitric oxide-dependent dilation to ACh, but not enhanced ET-1 vasoconstriction, in GFA from OPA animals. Conversely, vasoreactivity of SFAs to ACh and ET-1 were principally similar in all groups, whereas dilation to sodium nitroprusside was enhanced in OSED and OPA rats. These data demonstrate, for the first time, that SFAs from insulin-resistant rats exhibit reduced vulnerability to dysfunction versus GFAs and that physical activity largely prevents GFA dysfunction. We conclude that these results demonstrate that vascular dysfunction associated with insulin resistance is heterogeneously distributed across skeletal muscle vasculatures related, in part, to muscle fiber type and activity level.

Regional variation in arterial stiffening and dysfunction in Western diet-induced obesity

“…Second, local hemodynamics may contribute to reduced coronary vulnerability to dysfunction with WD feeding. We have previously demonstrated that the soleus muscle, but not the gastrocnemius muscle, feed artery exhibits resistance to obesity-related endothelial dysfunction (7). This protection likely relates to the relatively higher blood flows through this vessel compared with the gastrocnemius, since the soleus is recruited regularly during standing/walking whereas the gastrocnemius is recruited during running.…”

“…This protection likely relates to the relatively higher blood flows through this vessel compared with the gastrocnemius, since the soleus is recruited regularly during standing/walking whereas the gastrocnemius is recruited during running. Accordingly, access to a running wheel prevented gastrocnemius feed artery endothelial dysfunction (7). A similar resistance to dysfunction may be conferred to the coronary artery versus the femoral, owing to the high coronary flows necessitated by the constantly working heart.…”

Endurance, interval sprint, and resistance exercise training: impact on microvascular dysfunction in type 2 diabetes

“…Data from our laboratory, using the Otsuka Long Evans Tokushima fatty (OLETF) rodent model of T2D, indicate that endothelium-dependent dilation (EDD), examined using pressurized myography, is blunted in a muscle fiber type-dependent manner (14,64,95). As illustrated in Fig.…”

“…Importantly, each of the aforementioned conditions (neuropathy, retinopathy, nephropathy, exercise intolerance, and glucose intolerance) is caused, in part, by microvascular dysfunction. Studies performed in humans with insulin resistance or T2D and in animal models of disease demonstrate that EX mediates local and systemic improvements in endothelial (14,27,28,93,95,(101)(102)(103) and smooth muscle function (14,27,95) indicated by improved vasodilator signaling. Exercise training also appears to attenuate microvascular rarefaction in skeletal muscle associated with insulin resistance (23,52,67,90,126).…”

Identification of genes whose expression is altered by obesity throughout the arterial tree

“…Notably, there is evidence that obesityrelated endothelial dysfunction and structural changes are not homogenous throughout the arterial tree. For example, studies using the hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of obesity demonstrate that the soleus feed artery (SFA) is more resistant to impairments in vasomotor activity (6) as well as more resistant to increases in intimamedia thickness (21) compared with the gastrocnemius feed artery (GFA). A possible explanation for the fundamental differences in vascular function and structure between the SFA and GFA may be related to differences in the fiber type of the perfused muscle and different recruitment patterns (3).…”