Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
Condition: Stroke; Inflammation
MeSH terms: Stroke; Inflammation
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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, tumor necrosis factor (TNF) and
      nuclear factor kappa beta (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 (VO2) 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.

      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 hemiparetic (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 vastus lateralis (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 real time (RT)- polymerase chain
      reaction (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, activities of daily living (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-paretic (NP) 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.
    

Intervention name(s): Velocity based treadmill training; Duration based treadmill training
Intervention type(s): Other; Other
Intervention description(s): 6 month of progressive treadmill walking with a safety harness and hand rail support to prevent falls. Treadmill speed is gradually progressed to meet the training heart rate goals for moderate aerobic exercise, when hemiparetic gait velocity can no longer be progressed, incline is added to achieve heart rate training goals. Progression is also based on participant's tolerance, abilities and safety.; 6 month of progressive treadmill walking with a safety harness and hand rail support to prevent falls. Treadmill duration is gradually progressed to meet the endurance goals for low aerobic intensity exercise, gait velocity and incline do not progress. Progression is based on participant's tolerance, abilities and safety.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: exercise; inflammation; motor performance; skeletal muscle; chronic stroke survivors; treadmill exercise