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 offunctional capacity in the elderly. Although aerobic exercise training is commonly prescribed tocounter endothelial dysfunction in the elderly, the rate of compliance to aerobic exercise trainingprograms is low, often due to their strenuous nature. Thus, clinically-significant improvementsin physical function are not obtained by many individuals placed on aerobic training programs.Thus, there is a need to develop feasible non-pharmacological interventions that enhance bloodflow capacity in this population or in high-risk patients who cannot perform moderate aerobicexercise. Low-load, prolonged-duration ankle dorsiflexion, which stretches the muscles of thecalf, is prescribed in patients with limited range of motion and to counter foot drop in post-strokepatients. Acute changes in muscle length alter muscle blood flow; therefore, it is likely thatrepeated, prolonged changes in muscle length, created by dorsiflexion splinting, alter theregulation of muscle blood flow, and represent a viable modality to augment endothelial functionand functional capacity in the elderly. Our preliminary results in a rat model of aging indicatethat a 3-wk program of daily prolonged-duration, ankle dorsiflexion splinting dramaticallyimproves endothelium-dependent vasodilation of resistance arteries of the soleus muscle. Theoverarching purpose of the proposed work is to test the hypothesis that performance of dailyankle dorsiflexion splinting improves endothelial function and lower leg muscle blood flow in theelderly. 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 lowerhindlimb muscles will be evaluated in vivo during acute splinting and immediately following splintremoval. 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 exvivo, and in vitro analysis of endothelial mechanisms that contribute to enhanced endothelium-dependent dilation will be investigated.
In Aim 2, we will test the hypothesis that daily ankledorsiflexion splinting (4 wks) improves endothelial function of the popliteal artery in sedentary,older human subjects. This work will determine whether a safe, non-invasive intervention(dorsiflexion splinting) can be used to improve leg blood flow in elderly individuals. In addition, aprogram of daily dorsiflexion splinting, if shown to improve endothelial function and muscleblood flow 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. Thegoal of this study is to determine whether daily ankle dorsiflexion splinting improves endothelialfunction and muscle blood flow in the aged lower leg. A rat model of aging will be used toidentify endothelial mechanisms that contribute to splinting-induced improvement of endothelialfunction in lower leg hindlimb muscles; and a clinical study will be performed to determinewhether daily ankle dorsiflexion splinting improves endothelial function of the popliteal artery inolder; 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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Florida State University
Other Basic Sciences
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