The purpose of this study is to first define whether abnormalities of skeletal muscle are related to the presence of inflammation and to poor motor performance and whether this can be modified by exercise interventions.
Background: Stroke is the leading cause of disability in the United States. Biological changes in hemiparetic skeletal muscle may further propagate the disability. The investigators report gross muscular atrophy and major shift to fast myosin heavy chain (MHC) isoform distribution in hemiparetic thigh that are related to reduced fitness and slow walking speed. The investigators also find elevated inflammatory mediators, TNFa and NFkB in the paretic thigh muscle. No prior studies have systematically examined the profile of hemiparetic muscle contractile proteins and their relationship to function and fitness after stroke. Furthermore, the molecular mechanisms underlying hemiparetic skeletal muscle atrophy and contractile protein abnormalities are unknown.
The investigators have investigated treadmill aerobic exercise (T-AEX), as a task-oriented training model. This exercise model can reverse the alterations in MHC profile in hemiparetic leg muscles after stroke. This T-AEX program also improves fitness levels, leg strength, and ambulatory performance in chronic stroke. Moreover, post hoc analyses our randomized treadmill exercise program show that specific features of the exercise prescription likely influence the nature of exercise-mediated adaptations. Specifically, The investigators find that the degree of training velocity progression predicts gains in VO2 peak, but not walking function. In contrast, increasing training duration is associated with improved 6-minute walking function, but not fitness gains. These findings provide initial evidence that cardiovascular metabolic adaptations are contingent upon advancing the training velocity, rather than training duration. These exercise-mediated changes in MHC profiles and inflammation might be extremely important in the context of muscle structure and function, ambulation and overall fitness.
Hypothesis: The investigators propose a randomized clinical study to investigate the hypothesis that in chronic stroke patients a 6 month velocity-based progressive T-AEX program is superior to duration-based progressive T-AEX for improving HP leg skeletal muscle contractile protein expression and reducing inflammatory markers to improve muscle function, fitness, and ambulation.
Specific Aims: 1) Determine whether skeletal muscle MHC isoform expression is altered and inflammatory mediators, TNF and markers of NFkB activation, present in the hemiparetic vastus lateralis muscle, compared the non-paretic leg and matched non-stroke control leg muscles, and related to muscle function, fitness, and gait performance. 2) Determine whether 6 months progressive T-AEX programs can attenuate this abnormal MHC profile and inflammatory mediators to improve muscle structure and function.
Methods: At baseline, bilateral VL biopsies are obtained from chronically disabled, stroke participants with hemiparetic gait to examine the HP and non-P thigh skeletal muscles for alterations in MHC isoforms, key muscle contractile protein, and evidence for inflammation (TNFa) and NFkB activation. Participants are randomized to 6 months of progressive velocity-based or duration-based T-AEX training. Repeat VL muscle biopsies are obtained in the HP limb only after exercise interventions to assess whether 6-month exercise rehabilitation can restore MHC profile and attenuate activation of inflammatory pathways. Expression of the specific MHC isoforms, TNF, and NFKB marker expression (mRNA and protein) are investigated in these muscle tissues by real-time RT-PCR, Western Blot analysis, and immunohistochemistry. The investigators will explore relationships between T-AEX mediated changes in MHC expression and inflammatory activation in skeletal muscle after stroke to improve muscle strength, muscle performance, fitness and activity levels, ADL performance, and gait deficit severity.
Anticipated Results and Relevance: The cross-sectional baseline data will provide the first systematic study of a substantial cohort of stroke patients to define the relationship between altered structural and contractile protein expression to both muscle physiology and clinical measures of muscle performance, metabolic fitness, and rehabilitation mobility outcomes. HP VL muscle will be directly compared to the non-P limb muscle within -subjects and to non-stroke reference controls, in order to better understand the scope of skeletal muscle inflammatory and metabolic abnormalities in the stroke population. The intervention results will allow us to determine the specific requirements of treadmill training that are optimal and crucial to produce the exercise-mediated adaptations in hemiparetic skeletal muscle that lead to improved rehabilitation outcomes to reduce the disability of chronic stroke.
- Chronic stroke treadmill exercise to improve function Other
Intervention Desc: 6 month of treadmill exercise with a safety harness to prevent falls. Exercise is gradually progressed in walking speed and time on treadmill based on individual participant's tolerance, abilities and safety. Stroke participants are randomized to a) walking longer duration or b) walking at faster speeds on a treadmill for 6 months. ARM 1: Kind: Experimental Label: 1 Description: Chronic hemiparetice stroke survivors randomized to velocity based treadmill training ARM 2: Kind: Experimental Label: 2 Description: Chronic hemiparetice stroke survivors randomized to duration based treadmill training ARM 3: Kind: Experimental Label: Arm 1 Description: Chronic hemiparetice stroke survivors randomized to velocity based treadmill training ARM 4: Kind: Experimental Label: Arm 2 Description: Chronic hemiparetice stroke survivors randomized to duration based treadmill training
- Allocation: Randomized
- Masking: Open Label
- Purpose: Treatment
- Endpoint: Efficacy Study
- Intervention: Parallel Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||Cardiovascular fitness (VO2 peak)||6 month||No|
|Secondary||Muscle strength||6 month||No|
|Secondary||Walking (step activity monitor, 10 meter walking speed, 6 minute walking distance||6 month||No|
|Secondary||Bilateral thigh muscle protein and inflammation||6 month||No|