Clinical trial NCT00387712: Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
Official title: Inflammatory Abnormalities in Muscle After Stroke: Effects of Exercise
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Stroke
Inflammation
Keywords: exercise
inflammation
motor performance
skeletal muscle
chronic stroke survivors
treadmill exercise
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2006-10-13
Enrollment: 99
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cardiovascular Fitness (VO2 Peak)
timeFrame: Baseline to 6 month
measure: Paretic Thigh Skeletal Muscle Myosin Heavy Chain Myosin Heavy Chain Isoform 2a
timeFrame: Baseline to 6 month
Secondary outcomes:
measure: 30 Foot Walk Time (Sec)
timeFrame: baseline to 6 month
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: VA Maryland Health Care System, Baltimore
state: Maryland
Study officials:
affiliation: VA Maryland Health Care System, Baltimore
name: Charlene Hafer-Macko, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ivey FM, Hafer-Macko CE, Macko RF. Exercise training for cardiometabolic adaptation after stroke. J Cardiopulm Rehabil Prev. 2008 Jan-Feb;28(1):2-11. doi: 10.1097/01.HCR.0000311501.57022.a8.
citation: Ivey FM, Hafer-Macko CE, Macko RF. Task-oriented treadmill exercise training in chronic hemiparetic stroke. J Rehabil Res Dev. 2008;45(2):249-59. doi: 10.1682/jrrd.2007.02.0035.
citation: Prior SJ, McKenzie MJ, Joseph LJ, Ivey FM, Macko RF, Hafer-Macko CE, Ryan AS. Reduced skeletal muscle capillarization and glucose intolerance. Microcirculation. 2009 Apr;16(3):203-12. doi: 10.1080/10739680802502423. Epub 2009 Feb 16.
citation: McKenzie MJ, Yu S, Macko RF, McLenithan JC, Hafer-Macko CE. Human genome comparison of paretic and nonparetic vastus lateralis muscle in patients with hemiparetic stroke. J Rehabil Res Dev. 2008;45(2):273-81. doi: 10.1682/jrrd.2007.02.0036.
citation: Ivey FM, Ryan AS, Hafer-Macko CE, Macko RF. Improved cerebral vasomotor reactivity after exercise training in hemiparetic stroke survivors. Stroke. 2011 Jul;42(7):1994-2000. doi: 10.1161/STROKEAHA.110.607879. Epub 2011 Jun 2.
citation: Ryan AS, Ivey FM, Prior S, Li G, Hafer-Macko C. Skeletal muscle hypertrophy and muscle myostatin reduction after resistive training in stroke survivors. Stroke. 2011 Feb;42(2):416-20. doi: 10.1161/STROKEAHA.110.602441. Epub 2010 Dec 16.
citation: Hafer-Macko CE, Ryan AS, Ivey FM, Macko RF. Skeletal muscle changes after hemiparetic stroke and potential beneficial effects of exercise intervention strategies. J Rehabil Res Dev. 2008;45(2):261-72. doi: 10.1682/jrrd.2007.02.0040.
citation: Ryan AS, Buscemi A, Forrester L, Hafer-Macko CE, Ivey FM. Atrophy and intramuscular fat in specific muscles of the thigh: associated weakness and hyperinsulinemia in stroke survivors. Neurorehabil Neural Repair. 2011 Nov-Dec;25(9):865-72. doi: 10.1177/1545968311408920. Epub 2011 Jul 6.
citation: Ivey FM, Stookey AD, Hafer-Macko CE, Ryan AS, Macko RF. Higher Treadmill Training Intensity to Address Functional Aerobic Impairment after Stroke. J Stroke Cerebrovasc Dis. 2015 Nov;24(11):2539-46. doi: 10.1016/j.jstrokecerebrovasdis.2015.07.002. Epub 2015 Aug 21.