| Purpose: |
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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.
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| Study Summary: |
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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)
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. 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.
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