Resistance Exercise in Barth Syndrome

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.

Inclusion Criteria:

1. Age 15-35 years

2. Sedentary (exercises less than 2x/wk)

3. Motivated to exercise (BTHS only)

4. Stable on medications for ≥ 3 months (BTHS only)

5. Lives in North America

6. Lives in the St. Louis area (Controls only)

Exclusion Criteria:

1. Unstable heart disease

2. Cardiac transplantation