Resistance Exercise in Barth Syndrome
Condition: Barth Syndrome
MeSH terms: Barth Syndrome; Syndrome
Study type: Interventional

Summary: 
      Barth syndrome (BTHS) is a disorder that is characterized by heart failure, exercise
      intolerance and skeletal muscle weakness. Preliminary evidence demonstrates that endurance
      exercise training does not significantly improve exercise tolerance in BTHS. Because
      endurance exercise training targets a metabolic pathway that is adversely affected by BTHS,
      the investigators hypothesized that resistance training may improve exercise tolerance in
      BTHS because this type of training targets a different metabolic pathway than does endurance
      exercise. Therefore, the overall objective of the pilot/feasibility/proof-of-concept proposal
      is to collect preliminary data on the following hypothesis: Supervised resistance exercise
      training (3x/wk, 45min, 12 wks) will improve exercise tolerance, heart function, muscle
      strength and quality of life, and will be found safe in adolescents and young adults with
      BTHS.
    

Detailed description: 
      Barth syndrome (BTHS) is an X-linked disorder characterized by severe mitochondrial
      dysfunction, cardiomyopathy, skeletal muscle weakness and exercise intolerance. Preliminary
      evidence from our group has demonstrated that a 12-week endurance (i.e. aerobic) exercise
      training program increases exercise tolerance only modestly (~5%) in participants with BTHS
      with no effect on heart or skeletal muscle function. Other populations, including non-BTHS
      heart failure, appear to receive a greater benefit from endurance exercise training (e.g.
      ~15-25% increase in exercise tolerance) than does BTHS. The blunted effect of endurance
      exercise training in BTHS may be due to the inherent pathogenesis of BTHS: genetic
      mitochondrial dysfunction in type I (oxidative>glycolytic capacity) muscle fibers. Endurance
      exercise training typically results in increased mitochondrial density and enzyme function
      (primarily in type I muscle fibers) in other populations; however, in BTHS, due to maternally
      inherited mitochondrial dysfunction, endurance exercise training may result in the generation
      of more impaired mitochondria thus limiting any beneficial effect of endurance training on
      exercise tolerance. Thus, it may be more beneficial to target type II (glycolytic>oxidative
      capacity) muscle fibers with exercise training when attempting to increase exercise tolerance
      in BTHS. Indeed, previous evidence from non-BTHS heart failure has shown that resistance
      exercise training (RET) increases exercise tolerance, skeletal muscle strength, and heart
      function and improves quality of life in these individuals. Currently it is unknown if RET is
      effective in improving these variables in those with BTHS and is the focus of this proposal.
      Establishing the safety and efficacy of RET in BTHS could lead to clinical recommendations of
      regular RET instead of or in combination with endurance exercise training for the standard of
      care treatment of individuals with BTHS. Therefore, the overall objective of the
      pilot/feasibility/proof-of-concept proposal is to collect preliminary data on the following
      hypothesis: Supervised RET (3x/wk, 45min, 12 wks) with diet standardization (meeting at least
      minimum RDA recommendations for adolescents/young adults- 52-56 g protein/day) and protein
      supplementation (whey protein isolate, 42 g/day, Unjury Medical Quality Protein, Reston, VA )
      will improve exercise tolerance, left ventricular function, muscle strength and quality of
      life, and will be found safe in adolescents and young adults with BTHS. In addition, our
      preliminary data suggest there is impaired protein metabolism and skeletal muscle atrophy in
      BTHS. Typically, in other populations, whole-body and skeletal muscle protein synthesis
      increases with RET; however, this is unclear in BTHS. Thus, as a secondary aim, we will
      examine the effect of RET on whole-body protein metabolism in BTHS. We aim to address these
      hypotheses through left ventricular function, skeletal muscle strength, body composition,
      exercise tolerance, and whole-body protein metabolism measurements at baseline and following
      a 3 month supervised RET program in 3 participants with BTHS (ages 15-30 yrs). Supervised RET
      programs will be uniformly designed, but individualized and performed at a physical therapy
      or cardiac rehabilitation facility near the participant's home. Protein supplementation (whey
      protein isolate, 42 g/day) will be ingested by the participants in conjunction with the RET
      program. Nutritional status will be evaluated at baseline, mid-training (6-weeks) and
      post-training through plasma levels of pre-albumin and amino acid profile. Left ventricular
      function will be examined using 2-D, Doppler and tissue Doppler echocardiography, skeletal
      muscle strength will be measured using isotonic and isokinetic dynamometry, body composition
      using dual energy x-ray absorptiometry, exercise tolerance will be measured using graded
      exercise testing and indirect calorimetry, whole-body protein metabolism by stable-isotope
      tracer methodology and mass spectrometry, and quality of life will be measured by the
      Minnesota Living with Heart Failure Questionnaire. We expect to find that RET is safe in
      BTHS, and effectively improves cardiac function, skeletal muscle strength and mass,
      whole-body protein synthesis and quality of life. Preliminary data from this proposal will be
      used in larger federal or association grant applications examining the cardiovascular,
      musculoskeletal and protein metabolic effects of RET in BTHS.
    

Intervention name(s): Resistance exercise and protein supplementation
Intervention type(s): Behavioral
Intervention description(s): Resistance exercise training will occur 3x/wk for 12 wks at a physical therapy or cardiac rehabilitation facility near the participant's home. Participant will take 42 grams of supplementation protein daily.
Intervention model: Single Group Assignment
Intervention model description: Resistance exercise training
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: exercise; strength; training; barth syndrome; mitochondria; amino acid; protein