Endothelial function of the skeletal muscle resistance vasculature declines with advancing age, contributing to maldistribution of muscle blood flow during physical activity and a loss of functional capacity in the elderly. Although aerobic exercis training is commonly prescribed to counter endothelial dysfunction in the elderly, the rate of compliance to aerobic exercise training programs is low, often due to their strenuous nature. Thus, clinically-significant improvements in physical function are not obtained by many individuals placed on aerobic training programs. There is a need to develop feasible non-pharmacological interventions that enhance blood flow capacity in this population or in high-risk patients who cannot perform moderate aerobic exercise. Low-load, prolonged-duration ankle dorsiflexion, which stretches the muscles of the calf, is prescribed in patients with limited range of motion and to counter foot drop in post-stroke patients. Acute changes in muscle length alter muscle blood flow;therefore, it is likely that repeated, prolonged changes in muscle length, created by dorsiflexion splinting, alter the regulation of muscle blood flow, and represent a viable modality to augment endothelial function and functional capacity in the elderly. Our preliminary results in a rat model of aging indicate that a program of daily ankle dorsiflexion splinting dramatically improves endothelium- dependent vasodilation of resistance arteries of the soleus muscle. The overarching purpose of the proposed work is to test the hypothesis that performance of daily ankle dorsiflexion splinting improves endothelial function and lower leg muscle blood flow in the elderly. To test this hypothesis we will perform a preclinical study in aged Fischer rats (Aim 1), and clinical study in aged human subjects (Aim 2).
In Aim 1, blood flow distribution to the lower hindlimb muscles will be evaluated in vivo during acute splinting and immediately following splint removal. Following 4 wks of daily splinting, hindlimb muscle blood flow will be measured at rest, and during walking exercise. Endothelial function of resistance arteries will be assessed ex vivo, and analysis of endothelial mechanisms that contribute to enhanced endothelium-dependent dilation will be investigated.
In Aim 2, we will test the hypothesis that daily ankle dorsiflexion splinting (4 wks) improves endothelial function o the popliteal artery and lower leg resistance vasculature in sedentary, older human subjects. This work will determine whether a safe, non-invasive intervention (dorsiflexion splinting) can be used to improve endothelial function in elderly individuals. In addition, a program of daily dorsiflexion splinting, if shown to improve endothelial function in healthy older sedentary subjects, could be rapidly translated to clinical populations.

Public Health Relevance

Endothelial function, muscle blood flow, and muscle functional capacity decline with age. The goal of this study is to determine whether daily ankle dorsiflexion splinting improves endothelial function and muscle blood flow in the aged lower leg. A rat model of aging will be used to identify endothelial mechanisms that contribute to splinting-induced improvement of endothelial function in lower leg hindlimb muscles, and a clinical study will be performed to determine whether ankle dorsiflexion splinting improves endothelial function of the popliteal artery and calf resistance vessels in older, sedentary human subjects.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Joseph, Lyndon
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University of Florida
Schools of Medicine
United States
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Muller-Delp, Judy M; Hotta, Kazuki; Chen, Bei et al. (2018) Effects of age and exercise training on coronary microvascular smooth muscle phenotype and function. J Appl Physiol (1985) 124:140-149
Muller-Delp, Judy M; Gurovich, Alvaro N; Christou, Demetra D et al. (2012) Redox balance in the aging microcirculation: new friends, new foes, and new clinical directions. Microcirculation 19:19-28