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Background Obesity compromises cardiometabolic function and is associated with hypertension and chronic kidney disease. Exercise ameliorates these conditions, even without weight loss. Although the mechanisms of exercise's benefits remain unclear, augmented lean body mass is a suspected mechanism. Myostatin is a potent negative regulator of skeletal muscle mass that is upregulated in obesity and downregulated with exercise. The current study tested the hypothesis that deletion of myostatin would increase muscle mass and reduce blood pressure and kidney injury in obesity. Methods and Results Myostatin knockout mice were crossed to db/db mice, and metabolic and cardiovascular functions were examined. Deletion of myostatin increased skeletal muscle mass by ≈50% to 60% without concomitant weight loss or reduction in fat mass. Increased blood pressure in obesity was prevented by the deletion of myostatin, but did not confer additional benefit against salt loading. Kidney injury was evident because of increased albuminuria, which was abolished in obese mice lacking myostatin. Glycosuria, total urine volume, and whole kidney NOX-4 levels were increased in obesity and prevented by myostatin deletion, arguing that increased muscle mass provides a multipronged defense against renal dysfunction in obese mice. Conclusions These experimental observations suggest that loss of muscle mass is a novel risk factor in obesity-derived cardiovascular dysfunction. Interventions that increase muscle mass, either through exercise or pharmacologically, may help limit cardiovascular disease in obese individuals.

Objective: Many types of vascular smooth muscle cells exhibit prominent KDR currents. These KDR currents may be mediated, at least in part, by KV1.5 channels, which are sensitive to inhibition by DPO-1. We tested the hypothesis that DPO-1-sensitive KDR channels regulate the tone and reactivity of resistance-sized vessels from rat brain (MCA) and skeletal muscle (GA)., Methods: Middle cerebral and gracilis arteries were isolated and subjected to three kinds of experimental analysis: (i) western blot/immunocytochemistry; (ii) patch clamp electrophysiology; and (iii) pressure myography., Results: Western blot and immunocytochemistry experiments demonstrated KV1.5 immunoreactivity in arteries and smooth muscle cells isolated from them. Whole-cell patch clamp experiments revealed smooth muscle cells from resistance-sized arteries to possess a KDR current that was blocked by DPO-1. Resistance arteries constricted in response to increasing concentrations of DPO-1. DPO-1 enhanced constrictions to PE and serotonin in gracilis and middle cerebral arteries, respectively. When examining the myogenic response, we found that DPO-1 reduced the diameter at any given pressure. Dilations in response to ACh and SNP were reduced by DPO-1., Conclusion: We suggest that KV1.5, a DPO-1-sensitive KDR channel, plays a major role in determining microvascular tone and the response to vasoconstrictors and vasodilators., (© 2015 John Wiley & Sons Ltd.)

Objective: To determine HMV and PS in skeletal muscle of OZR and evaluate the impact of increased microvascular perfusion heterogeneity on mass transport/exchange., Methods: The in situ gastrocnemius muscle from OZR and LZR was examined under control conditions and following pretreatment with TEMPOL (antioxidant)/SQ-29548 (PGH2 /TxA2 receptor antagonist), phentolamine (adrenergic antagonist), or all agents combined. A spike input of a labeled blood tracer cocktail was injected into the perfusing artery. Tracer washout was analyzed using models for HMV and PS. HT was determined in in situ cremaster muscle of OZR and LZR using videomicroscopy., Results: HMV was decreased in OZR versus LZR. While TEMPOL/SQ-29548 or phentolamine had minor effects, treatment with all three agents improved HMV in OZR. HT was not different between strains, although variability was increased in OZR, and normalized following treatment with all three agents. PS was reduced in OZR and was not impacted by intervention., Conclusions: Increased microvascular perfusion heterogeneity in OZR reduces HMV in muscle vascular networks and increases its variability, potentially contributing to premature muscle fatigue. While targeted interventions can ameliorate this, the reduced microvascular surface area is not acutely reversible., (© 2014 John Wiley & Sons Ltd.)

Objective: To use the OZR model of the metabolic syndrome to determine the impact of dilator stimuli on MA of GA and MCA. We tested the hypothesis that increased oxidant stress and TxA2 exacerbate MA, and prevent its blunting with dilator stimuli, in OZR., Methods: GA/MCA from OZR and LZR was pressurized ex vivo. MA was determined under control conditions and following challenge with acetylcholine, hypoxia, and adenosine. Responses were also evaluated after pre-treatment with TEMPOL (antioxidant) and SQ-29548 (PGH2 /TxA2 receptor antagonist)., Results: MA was increased (and dilator responses decreased) in GA/MCA from OZR, dependent on the endothelium and ROS. In GA, the impact of ROS on MA and dilator effects was largely via TxA2 , while in MCA, this appeared was more dependent on NO bioavailability. Intrinsic responses of GA/MCA to carbacyclin, U46619, and NO donors were similar between strains., Conclusions: A developing ROS-based endothelial dysfunction in MCA and GA of OZR contributes to an enhanced MA of these vessels. Although treatment of GA/MCA with TEMPOL attenuates MA in OZR, the mechanistic contributors to altered MA, distal to ROS, differ between the two resistance vessels., (© 2013 John Wiley & Sons Ltd.)

The metabolic syndrome is associated with elevated peripheral vascular disease risk, characterized by mismatched blood flow delivery/distribution and local metabolism. The obese Zucker rat (OZR) model of the metabolic syndrome exhibits myriad vascular impairments, although their integrated impact on functional hyperaemia remains unclear. In this study, arterial pressor responses and skeletal muscle perfusion were assessed in lean Zucker rats (LZRs) and OZRs during adrenergic stimulation (phenylephrine), challenge with thromboxane (U46619) and endothelium-dependent dilatation (methacholine). The OZRs were hypertensive compared with the LZRs, but this was abolished by adrenoreceptor blockade (phentolamine); pressor responses to U46619 were similar between strains and were abolished by blockade with the prostaglandin H(2)/thromboxane A(2) receptor antagonist, SQ-29548. Depressor reactivity to methacholine was impaired in OZRs, but was improved by antioxidant treatment (TEMPOL). Across levels of metabolic demand, blood flow to in situ gastrocnemius muscle was restrained by adrenergic constriction in OZRs, although this diminished with increased demand. Oxygen extraction, reduced in OZRs compared with LZRs across levels of metabolic demand, was improved by TEMPOL or SQ-29548; treatment with phentolamine did not impact extraction, and neither TEMPOL nor SQ-29548 improved muscle blood flow in OZRs. While oxygen uptake and muscle performance were consistently reduced in OZRs versus LZRs, treatment with all three agents improved outcomes, while treatment with individual agents was less effective. These results suggest that contributions of vascular dysfunction to perfusion, oxygen uptake and muscle performance are spatially distinct, with adrenergic constriction impacting proximal resistance and endothelial dysfunction impacting distal microvessel-tissue exchange. Further, these data suggest that increasing skeletal muscle blood flow in OZRs is not sufficient to improve performance, unless distal perfusion inhomogeneities are rectified.