Targeting the muscle metaboreflex to optimize exercise capacity in stroke survivors - stroke survivors are unable to adequately increase and sustain cardiovascular drive during exercise, which…

The National Institute of Child Health and Human Development awarded The Medical College of Wisconsin, Inc., $1,318,677 on September 15, 2025, under the Child Health and Human Development Extramural Research program (CFDA 93.HDR) to conduct research on the muscle metaboreflex mechanism in stroke survivors.

The research investigates why stroke survivors cannot adequately increase and sustain cardiovascular drive during exercise, limiting their capacity to exercise at high intensity. The project focuses on dysregulation of sympathetic reflex pathways during exercise in stroke survivors. Aim 1 establishes whether the muscle metaboreflex is impaired in the paretic leg compared to the non-paretic leg and matched controls, and tests the hypothesis that metaboreflex activation correlates with voluntary muscle activation and metabolite concentration during muscle contractions. Aim 2 determines the relationship between metaboreflex function and exercise capacity. This research addresses a clinical gap, as recent studies show that high-intensity exercise training at 70 percent heart rate reserve produces large motor gains post-stroke, yet stroke survivors struggle to achieve and sustain the heart rates necessary for such training.

Work is performed in Wauwatosa, Wisconsin, with a period of performance extending from September 15, 2025, through May 31, 2030. The award is a Project Grant (assistance type).

Marquette University serves as a sub-recipient, receiving a sub-award dated March 13, 2026, to contribute to the research on the muscle metaboreflex and exercise capacity in stroke survivors.

Targeting the muscle metaboreflex to optimize exercise capacity in stroke survivors - stroke survivors are unable to adequately increase and sustain cardiovascular drive during exercise, which limits their capacity to exercise at high intensity. This is clinically meaningful because recent studies indicate that high intensity exercise training (≥70% heart rate reserve, HRR) causes large motor gains post-stroke. However, a central challenge is getting stroke survivors to achieve and sustain sufficiently high heart rates to exercise at high intensity, and sessions can be limited to short bouts of exercise versus a continuous effort. An overlooked mechanism of reduced exercise capacity post-stroke is the dysregulation of sympathetic reflex pathways during exercise. When muscles become metabolically active, metabolites accumulate in the muscle. These metabolites are sensed by group III/IV afferent nerves, which signal to brain centers to increase sympathetic outflow, resulting in increases in cardiovascular drive to maintain adequate blood flow to the exercising muscle. Activation of this "metaboreflex" is thus vital to drive the proper hemodynamic response to exercise. Our central hypothesis is that in stroke survivors reduced activation of skeletal muscle in the paretic leg results in an impaired metaboreflex during exercise, limiting exercise capacity. In aim 1 we will establish impairment of the muscle metaboreflex in chronic stroke survivors and determine the relationship with voluntary muscle activation and muscle metabolite accumulation during exercise. We will test two hypotheses, 1) that the muscle metaboreflex is impaired in the paretic leg compared to the non-paretic leg and VS. Matched controls, and 2) that in the paretic leg, the magnitude of metaboreflex activation will be positively correlated with voluntary activation of the muscle and the concentration of metabolites during muscle contractions. In aim 2 we will determine the relationship between metaboreflex activation and exercise capacity, and test two hypotheses, 1) that there will be a positive relationship between the magnitude of metaboreflex activation and both maximum heart rate and peak workload during a graded exercise test, and 2) that stroke survivors with greater metaboreflex activation in the paretic leg can spend more time exercising at ≥70 % of their HRR during a high intensity walking task. Finally, in aim 3 we propose a prospective, randomized, controlled, double-blinded crossover clinical trial designed to determine if ischemic conditioning (IC) can improve metaboreflex activation in the paretic muscle and whether improvements result in better performance during a high intensity walking task. We will test two hypotheses, 1) that in chronic stroke survivors IC causes acute improvements in muscle metaboreflex activation and increases the time spent exercising at heart rates ≥70% HRR during a high intensity walking task, and 2) that following IC, stroke survivors with the largest increases in metaboreflex activation also show the largest increases in time spent exercising at heart rates ≥70 % HRR during the walking task. Successful completion of this study could identify impairment of the metaboreflex pathway as a primary cause for reduced cardiovascular drive during exercise post-stroke and establish IC as a rehabilitation adjunct to optimize the cardiovascular response to exercise in stroke survivors.