Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise

June 22, 2017 updated by: VA Office of Research and Development
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

99

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • VA Maryland Health Care System, Baltimore

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Chronic stroke (>6 months after initial stroke)
  • Age 40-80
  • Stable neurologic deficits
  • Able to walk with an assistive device
  • Language skills to understand the training program safely

Exclusion Criteria:

  • No anticoagulation or medical conditions that preclude exercise.
  • No dementias or depression

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Velocity based treadmill training
6 month of progressive treadmill walking with treadmill speed gradually progressed to meet the training heart rate goals for moderate intensity aerobic exercise, when hemiparetic gait velocity can no longer be safely progressed, incline is added to achieve the heart rate training goals.
Other: Velocity based treadmill training
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.
Experimental: Duration based treadmill training
6 month of progressive treadmill walking with duration is gradually progressed to meet the endurance goals for low aerobic intensity exercise, gait velocity and incline do not progress.
Other: Duration based treadmill training
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cardiovascular Fitness (VO2 Peak)
Time Frame: Baseline to 6 month
Cardiovascular fitness is measured by collecting the expired gases during a progressive graded treadmill test.
Baseline to 6 month
Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a
Time Frame: Baseline to 6 month
Skeletal muscle punch biopsies are obtained from the bilateral (paretic and non-paretic) vastus lateralis thigh muscle, at baseline and after 6 month interventions. Homogenized muscle messenger ribonucleic acid (mRNA) for myosin heavy chain isoforms are analyzed by real time polymerase chain reaction as fluorescent units with normalization to an acidic ribosomal protein, a housekeeping gene.
Baseline to 6 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
30 Foot Walk Time (Sec)
Time Frame: baseline to 6 month
Participants are instructed to walk fast as comfortable on a straight pathway on the floor demarcated by cones. They may use their usual canes, walkers, and orthotics while they walk. The walks are timed, the value is the mean of three trials with an interval rest between each trial.
baseline to 6 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Investigators

  • Principal Investigator: Charlene Hafer-Macko, MD, VA Maryland Health Care System, Baltimore

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2006

Primary Completion (Actual)

August 1, 2012

Study Completion (Actual)

August 1, 2014

Study Registration Dates

First Submitted

October 12, 2006

First Submitted That Met QC Criteria

October 12, 2006

First Posted (Estimate)

October 13, 2006

Study Record Updates

Last Update Posted (Actual)

September 14, 2017

Last Update Submitted That Met QC Criteria

June 22, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • B3834-R

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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