Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Strength Training for Skeletal Muscle Adaptation After Stroke

Summary: Chronically disabled stroke survivors experience accelerated skeletal muscle atrophy and other detrimental changes to muscle and surrounding tissues on the paretic side. This unilateral tissue-level damage contributes to worsening disability and insulin resistance. This VA Merit Award will advance the investigators' understanding of the potential for strength training (ST) to reverse stroke-related muscle abnormalities to improve metabolic health, strength, and function. It will be the first study to thoroughly investigate the effects of ST on muscle atrophy, intramuscular fat, muscle fiber characteristics, capillary density and insulin sensitivity after stroke.

Detailed description: This study investigates the hypothesis that a novel, high intensity, high repetition ST program will improve abnormalities in paretic and non-paretic leg muscle volume and composition compared to an attention-matched control regimen of supervised stretching over a 3-month intervention period in those disabled by stroke. The investigators further hypothesize that ST-induced skeletal muscle adaptation will translate into improved insulin sensitivity, strength, and function in this population. The specific objectives are to: 1) Determine the effects ST compared to a control intervention on paretic and non-paretic abnormalities in skeletal muscle volume, intramuscular fat, muscle fiber distribution, muscle capillary density, and muscle inflammation in chronically disabled stroke survivors. 2) Determine the effects ST compared to a control intervention on insulin sensitivity in stroke survivors, and whether structural and cellular skeletal muscle mechanisms contribute to improvements in insulin sensitivity after ST. 3) Determine the effects ST compared to a control intervention on physical function (strength, walking speed and balance) in stroke survivors, and whether structural skeletal muscle mechanisms predict ST-induced functional improvement.
  The project design consists of 4 phases over 5 months for stroke participants enrolled in either of the two intervention arms (ST vs. CONTROL). During phase 1 the investigators will screen and consent chronic stroke patients with residual gait deficits. Phase 2 (3 weeks) will consist of baseline testing that includes dual energy X-ray absorptiometry (DEXA) scanning, bilateral CT scanning of the legs, bilateral vastus lateralis muscle biopsies, strength testing, timed walks, balance measurements, oral glucose tolerance testing, and hyperglycemic clamp testing. Following completion of baseline testing, volunteers are to be randomized to ST or the CONTROL group. Phase 3 (Intervention Phase, 3 months) will begin with 2 sessions of acclimatization for those assigned to the ST group. ST will then be progressed to 2 sets of 20 repetitions on each leg on each machine (Keiser Leg Press, Leg Extension, Leg Curl) with gradual increases in resistance over 3 months. Those in the CONTROL group will receive equal exposure to health care personnel in the Baltimore VA Exercise facility, performing a full battery of upper and lower body passive and active stretching exercises at each intervention session. In Phase 4 all baseline testing and laboratory analyses will be repeated.
  Developing evidence-based therapies to combat skeletal muscle deterioration is highly relevant for chronically disabled stoke survivors. There is mounting evidence that current models of post-stroke rehabilitation are not optimal for maximizing recovery of muscle mass, strength, and metabolic health. The proposed research will develop new insight into the utility of progressive ST for reversing detrimental changes to gross muscle composition, muscle molecular phenotype, muscle inflammation, and muscle capillarization. Changes to any or all of these muscle parameters should have measurable impact on both whole body insulin sensitivity and function. Collectively, the results from this trial may change the current standard of care for stroke survivors by providing evidenced reasons for augmenting physical therapists' treatments, allowing more intense and diverse therapy sessions for maintenance of skeletal muscle.

Eligibility: Inclusion Criteria:
  -  Stroke greater than 6 months prior with residual hemiparetic gait in women or men aged 40-85 years
  -  Completion of all regular post-stroke physical therapy
  -  Adequate language and neurocognitive function to participate in testing and training and to give adequate informed consent
  Exclusion Criteria:
  -  Alcohol consumption greater than 3 oz. liquor, or 3 x 4 oz glasses of wine, or 3 x 12 oz. beers per day, by self-report
  -  clinical history of:
  -  unstable angina
  -  recent (less than 3 months) myocardial infarction or congestive heart failure (NYHA category II)
  -  hemodynamically significant valvular dysfunction
  -  peripheral arterial occlusive disease (PAOD) with claudication
  -  major orthopedic, chronic pain, or non-stroke neuromuscular disorders restricting exercise
  -  pulmonary or renal failure
  -  poorly controlled hypertension (greater than 190/110)
  -  recent hospitalization for severe disease or surgery
  -  severe or global receptive aphasia which confounds reliable testing and training
  -  Allergy to lidocaine
  -  Known muscle disorder
  -  Taking Coumadin or Lovenox (contraindication for muscle biopsies)
  -  Dementia
  -  Untreated major depression

Relevance to patient case: not relevant