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

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; angiogenesis; cardiovascular; resistance exercise; skeletal muscle.

Figure 1.

(A) Experimental timeline. (B) Infarct volume. (C) Representative magnetic resonance image of median infarct; stroke delineated in red; 1000-µm scale bar. Hindlimb function was assessed on the (D) beam traversal task and (E) through kinematic assessment of gait. (F) Left panel: stroke resulted in increased foot faults on the beam traversal task over time (n = 9). Middle panel: exercise rehabilitation improved beam performance (Time × DEx; n = 16-18). Right panel: resveratrol resulted in less foot faults at week 1 and week 6 poststroke (Time × Resv; n = 16-18). (G) Left panel: duration of time spent in shared stance during gait (n = 6-9). Right panel: Resv prevented the development of increased shared stance time (Time × Resv; n = 15-17). (H) Left panel: rats developed a wider stance width at week 6 compared with week 1 poststroke (n = 6-9). Right panel: overall, rats that received Resv had a narrower stance width (n = 29-32). Abbreviations: Resv, resveratrol; Sed Veh, sedentary vehicle control; Sed Resv, sedentary Resv; DEx Veh, exercise vehicle; DEx Resv, exercise Resv. ^a Different from prestroke. ^b Different from 1 week poststroke. ^c Different from 3 weeks poststroke. * P < .05.

Figure 2.

Resveratrol increased vascular density in the ipsilesional hemisphere. (A) Representative image of infarct with NeuroTrace (red) and ROI areas that were sampled; 1000-µm scale bar. Inset: Representative image of delineated infarct area; 250-µm scale bar. (B) Representative CD31 (green) images within the sedentary Resv group; 100-µm scale bar. (C) Vessel length in the cortex was similar between groups and independent of hemisphere (n = 7-9). (D) Sedentary Resv had more vascular branch points in the ipsilesional compared with the contralesional hemisphere (n = 7-9). (E) Vascular branch points were increased in the ipsilesional hemisphere compared with the contralesional hemisphere (n = 34). Abbreviations: Resv, resveratrol; Sed Veh, sedentary vehicle control; Sed Resv, sedentary Resv; DEx Veh, exercise vehicle; DEx Resv, exercise Resv; ROI, region of interest. * P < .05.

Figure 3.

Stroke resulted in decreases in cardiovascular fitness, which was attenuated with delayed exercise. (A) Left panel: stroke reduced VO2 peak during a maximal exercise test (n = 5-9). Right panel: The exercise rehabilitation attenuated further reductions in VO2 peak (Time × DEx; n = 13-17). (B) Left panel: the distance rats could run until exhaustion was reduced at week 1 and week 6 poststroke (n = 5-9). Right panel: rats that engaged in the exercise rehabilitation could run farther until exhaustion at week 3 and week 6 poststroke compared with being sedentary (Time × DEx; n = 13-17). (C) The delayed exercise rehabilitation was a combination of resistance (ladder climbing) and aerobic (treadmill) exercise. (D) Left panel: PGC1α protein content in the red portion of the tibialis anterior (n = 7-8). Right panel: exercise increased PGC1α protein content, indicative of increased aerobic metabolism (n = 15-16). Lower panel: representative Western blot image. Abbreviations: Resv, resveratrol; Sed Veh, sedentary vehicle control; Sed Resv, sedentary Resv; DEx Veh, exercise vehicle; DEx Resv, exercise Resv; VO2 peak, peak oxygen consumption; PGC1α, proliferator-activated receptor gamma coactivator 1-α. ^a Different from prestroke. ^bDifferent from 1 week poststroke. ^*P < .05.

Figure 4.

Stroke resulted in mild atrophy throughout the plantaris muscle. (A) Representative image of skeletal muscle fiber types. Left panel: cross section of plantaris muscle with type I (blue), type IIa (green), type IIx (unlabeled), and type IIb (red) muscle fibers; scale bar 1000 µm. Right panel: region depicted in white box; scale bar 300 µm. (B) Left panel: wet mass of plantaris muscle (n = 8-9). Right panel: resveratrol increased the mass of the plantaris muscle independent of limb or exercise. (n = 34-36). (C) Left panel: cross-sectional area (CSA) of plantaris muscle belly (n = 8-9). Right panel: stroke resulted in atrophy of the plantaris muscle in the affected limb independent of Resv or exercise. (D) Left panel: difference in CSA of plantaris muscle between affected and unaffected limb (n = 7-9). Right panel: there was a trend that Resv mitigated atrophy of the affected plantaris muscle (n = 17). (E-H) Proportion of type I, type IIa, type IIx, and type IIb skeletal muscle fibers (n = 8-9). Abbreviations: Resv, resveratrol; Sed Veh, sedentary vehicle control; Sed Resv, sedentary Resv; DEx Veh, exercise vehicle; DEx Resv, exercise Resv. *P < .05.

Figure 5.

Stroke resulted in significant changes to muscle fiber cross-sectional area (CSA) that was improved with Resv and exercise. (A-D) Left panel: cumulative frequency distributions of the CSA of skeletal muscle fiber types revealed that the distribution of type I, IIa, IIx, and IIb fiber CSA was different between limbs in sedentary vehicle rats. The affected limb had larger type I, IIa, and IIx fibers and smaller type IIb fibers than the unaffected limb. Right panel: median CSA of each fiber type between limbs in sedentary vehicle. (E-H) Both Resv and exercise normalized changes to muscle fiber CSA. Data represent the median CSA of each muscle fiber type in the affected plantaris muscle. Dashed line, median fiber area in the unaffected plantaris muscle of sedentary vehicle (ie, control). Abbreviations: Resv, resveratrol; Sed Veh, sedentary vehicle control; Sed Resv, sedentary Resv; DEx Veh, exercise vehicle; DEx Resv, exercise Resv. ^a,b,c Represents groups with homogeneous frequency distributions; P > .05. ^# Indicates homogeneous frequency distribution with the unaffected plantaris muscle in sedentary vehicle (ie, control). *** P < .001. Fiber distributions were compiled from n = 8-9.