With metabolic syndrome (MS) in obese Zucker rats (OZR), the ability of in situ skeletal muscle to resist fatigue is compromised well before muscle function; implicating microvascular or perfusion-based impairments as playing a causal role. However, our results suggest that bulk flow to muscle is not sufficiently constrained to explain the poor performance, and indices such as dilator/constrictor reactivity, vessel wall mechanics and capillary density are not strong predictors of functional outcomes. We have determined that altered RBC distribution at arteriolar bifurcations (?) is increasingly heterogeneous in OZR muscle, iterating to produce a wide heterogeneity of pre-capillary flow distribution vs. controls. This increased spatial heterogeneity of perfusion at bifurcations is not compensated for via temporal switching, rather it is exacerbated owing to blunted temporal activity. The combined effect of these behaviors is that microvascular hematocrit becomes increasingly heterogeneous and fixed, compromising perfusion:demand matching and muscle performance. The magnitude of the deviation of ? from 0.5, and its temporal stability are the strongest predictors of muscle performance to date and reflect a striking loss of system flexibility for microvascular responses to imposed challenges under the setting of elevated cardiovascular disease risk.