An Exercise Mimetic Approach to Reduce Poststroke Deconditioning and Enhance Stroke Recovery

 I'm sure your eyes immediately glassed over upon seeing the word 'mimetic'.

An Exercise Mimetic Approach to Reduce Poststroke Deconditioning and Enhance Stroke Recovery

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Matthew W. McDonald, PhD, Matthew S. Jeffers, MSc, Lama Issa, ...

First Published April 7, 2021 Research Article 

https://doi.org/10.1177/15459683211005019

Article information

Abstract

Evidence supports early rehabilitation after stroke to limit disability. However, stroke survivors are typically sedentary and experience significant cardiovascular and muscular deconditioning. Despite growing consensus that preclinical and clinical stroke recovery research should be aligned, there have been few attempts to incorporate cardiovascular and skeletal muscle deconditioning into animal models of stroke. Here, we demonstrate in rats that a hindlimb sensorimotor cortex stroke results in both cardiovascular and skeletal muscle deconditioning and impairments in gait akin to those observed in humans. To reduce poststroke behavioral, cardiovascular, and skeletal muscle perturbations, we then used a combinatorial intervention consisting of aerobic and resistance exercise in conjunction with administration of resveratrol (RESV), a drug with exercise mimetic properties. A combination of aerobic and resistance exercise mitigated decreases in cardiovascular fitness and attenuated skeletal muscle abnormalities. RESV, beginning 24 hours poststroke, reduced acute hindlimb impairments, improved recovery in hindlimb function, increased vascular density in the perilesional cortex, and attenuated skeletal muscle fiber changes. Early RESV treatment and aerobic and resistance exercise independently provided poststroke benefits, at a time when individuals are rapidly becoming deconditioned as a result of inactivity. Although no additive effects were observed in these experiments, this approach represents a promising strategy to reduce poststroke behavioral impairments and minimize deconditioning. As such, this treatment regime has potential for enabling patients to engage in more intensive rehabilitation at an earlier time following stroke when mechanisms of neuroplasticity are most prevalent.

Keywords aerobic exercise, resistance exercise, skeletal muscle, angiogenesis, cardiovascular

Introduction

With advances in acute care, stroke has transitioned from a disease of survivability to one of chronic disability.¹ To optimize behavioral recovery, preclinical evidence suggests that high-intensity rehabilitation should be initiated during the early subacute stroke recovery phase to harness the brain’s endogenous repair mechanisms.^2-5 Instead, at this time stroke patients are extremely inactive, spending more than 50% of their time lying in bed and ~87% of time in a sedentary state.^6,7 As such, stroke survivors experience significant deconditioning and fatigue, which reduces their capacity to engage in high-intensity rehabilitation and accomplish most activities of daily living.^8-11

International consensus groups recognize that preclinical and clinical research must become better aligned to advance the field of stroke recovery.^12,13 In humans, the stroke-affected limb undergoes significant muscular atrophy, hypertrophy of slow-twitch fibers, and atrophy of fast-twitch fibers.^8,9,14 Similarly, stroke survivors experience significant cardiovascular deconditioning.^8-11 Currently, these aspects of cardiovascular and skeletal muscle dysfunction have not been incorporated into animal models of stroke, nor has consideration been given to the idea that the benefits of poststroke interventions might be a result of central as well as peripheral actions.^8,9,11,14,15

Exercise is viewed as a powerful poststroke therapeutic, enhancing brain repair through multiple mechanisms such angiogenesis, upregulation of growth factors, reducing inflammation, and attenuating deteriorations in cardiovascular and skeletal muscle health.^11,16,17 However, implementing aerobic exercise following stroke is challenging, largely because of fatigue and deconditioning.^8,18 Thus, poststroke deconditioning is a significant barrier that limits patients’ ability to engage in early, intensive rehabilitation programs. A possible solution is to administer drugs that induce central and peripheral effects similar to physical exercise (ie, exercise mimetics). In this context, resveratrol (RESV), a naturally occurring polyphenol (found in grapes, blueberries, peanuts, etc), has the potential to enhance neurological recovery and attenuate poststroke cardiovascular and skeletal muscle deconditioning by activation of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), and angiogenesis in a variety of body tissues (eg, brain, heart, muscle) similar to exercise.^19-23

Because lack of mobility is such an important issue for patients following stroke, we used a rat model of hindlimb motor cortex stroke to assess poststroke changes in skeletal muscle and cardiovascular deconditioning. We hypothesized that both RESV and delayed aerobic and resistance exercise (DEx) following stroke would enhance behavioral recovery and attenuate poststroke deconditioning but that the combination would be most effective. In summary, this study aimed to address a number of interrelated research questions: (1) In conjunction with persistent hindlimb deficits, do rats experience cardiovascular deconditioning and skeletal muscle fiber changes as observed clinically? (2) Does early RESV administration reduce acute hindlimb deficits? (3) Does RESV alone or in combination with exercise rehabilitation improve long-term hindlimb recovery? (4) Does RESV alone or in combination with exercise mitigate perturbations in cardiovascular fitness and skeletal muscle after stroke?