Impaired cardiac reserve and severely diminished skeletal muscle O<sub>2</sub> utilization mediate exercise intolerance in Barth syndrome

Spencer, Carolyn T.; Byrne, Barry J.; Bryant, Randall M.; Margossian, Renée; Maisenbacher, Melissa; Breitenger, Petar; Benni, Paul B.; Redfearn, Sharon; Marcus, Edward; Cade, W. Todd

doi:10.1152/ajpheart.00479.2010

Cited by 79 publications

(130 citation statements)

References 44 publications

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“…All participants underwent echocardiography using a standardized protocol designed to evaluate LV size, LV morphology, and systolic and diastolic function as previously described (Spencer et al 2011). All echocardiograms were recorded digitally and each study participant and visit was interpreted and measured by the same cardiologist (CLT) who was blinded to subject identification.…”

Section: Echocardiographymentioning

confidence: 99%

“…Relative concentration changes in oxy-(HbO 2 ), deoxy-(DeoxyHb), and total (TotalHb) hemoglobin of the vastus lateralis muscle and brain were measured using a four-wavelength continuous wave NIRS system (FORE-SIGHT ® , CAS Medical Systems Inc., Branford, CT) as previously described (Spencer et al 2011). …”

Section: Near-infrared Spectroscopymentioning

confidence: 99%

“…Our group recently found that whole-body peak oxygen consumption (VO 2peak ) during acute exercise was significantly impaired in BTHS when compared to healthy peers (Spencer et al 2011). Further, deficits in VO 2peak in those with BTHS were mediated by impairments in both cardiac and skeletal muscle function (Spencer et al 2011).…”

mentioning

confidence: 99%

“…Further, deficits in VO 2peak in those with BTHS were mediated by impairments in both cardiac and skeletal muscle function (Spencer et al 2011). This is important because peak oxygen consumption (i.e., exercise tolerance) is the single best predictor of cardiovascular and all-cause mortality in individuals with cardiovascular disease (Myers et al 2002).…”

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Endurance Exercise Training in Young Adults with Barth Syndrome: A Pilot Study

et al. 2016

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Background: Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondrial abnormalities, cardio-skeletal myopathy, exercise intolerance, and premature mortality. The effect on endurance exercise training on exercise tolerance, cardio-skeletal function, and quality of life in BTHS is unknown.Methods: Four young adults (23 AE 5 years, n ¼ 4) with BTHS participated in a 12-week, supervised, individualized endurance exercise training program. Exercise training was performed on a cycle ergometer for 30-45 0 three times per week at a moderate intensity level.Exercise tolerance was measured by graded exercise testing and peak oxygen consumption, heart function via two-dimensional and M-mode echocardiography, skeletal muscle function by near-infrared spectroscopy, and quality of life through the Minnesota Living with Heart Failure questionnaire.Results: There were no adverse events during exercise testing or training for any participant. Peak oxygen consumption modestly (~5%) improved in three or four participants. Mean quality of life questions regarding dyspnea and side effects from medications significantly improved following exercise training. Mean resting heart function or skeletal muscle oxygen extraction during exercise did not improve after exercise training.Conclusion: Endurance exercise training is safe and appears to modestly improve peak exercise tolerance and certain measures of quality of life in young adults with BTHS. However, compared to improvements resulting from endurance exercise training seen in other non-BTHS mitochondrial myopathies and heart failure, these improvements appear blunted. Further research into the most beneficial mode, intensity and frequency of exercise training in BTHS is warranted.Barth syndrome (BTHS) is an X-linked disorder that results in cardio-skeletal myopathy, heart failure, fatigue, chronic/ cyclic neutropenia, growth delay, and premature mortality (Barth et al. 1983). The full scope of the pathological and clinical manifestations of BTHS is not fully understood, but involves a tafazzin gene defect that results in cardiolipin deficiency and severe mitochondrial dysfunction. BTHSassociated mitochondrial dysfunction is assumed to mediate the cardio-skeletal myopathy seen in the majority of those with BTHS (Spencer et al. 2006).

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Section: Echocardiographymentioning

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Section: Near-infrared Spectroscopymentioning

confidence: 99%

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Endurance Exercise Training in Young Adults with Barth Syndrome: A Pilot Study

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“…CL is also involved in the β-oxidation of fatty acids, as a reduction of mature CL impairs skeletal muscle FA oxidation [27,28] and a positive correlation has been demonstrated between mitochondrial COX activity and CL content [29]. Patients with Barth Syndrome (a X-linked disorder resulting from mutations in the gene encoding for tafazzin) or mice models which lack mature CL, have shown exercise intolerance, cardiac and skeletal muscle dysfunction, mitochondrial dysfunction, ATP deficiency and premature mortality [30,31,32] In vitro, mitochondrial respiration has been shown to be impaired in inducible pluripotent stem cell (iPSC)-derived human cardiomyocytes from Barth Syndrome patients [33]. Possible mechanisms for this disease-associated mitochondrial dysfunction include mitochondrial supercomplex destabilization [34], higher reduced levels of mitochondrial cardiolipin [35] and abnormal mitochondrial morphology [30].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

Baati

Feillet‐Coudray

Fouret

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Myostatin (Mstn) deficiency leads to skeletal muscle overgrowth and Mstn inhibition is considered as a promising treatment for muscle-wasting disorders. Mstn gene deletion in mice also causes metabolic changes with decreased mitochondria content, disturbance in mitochondrial respiratory function and increased muscle fatigability. However the impact of MSTN deficiency on these metabolic changes is not fully elucidated. Here, we hypothesized that lack of MSTN will alter skeletal muscle membrane lipid composition in relation with pronounced alterations in muscle function and metabolism. Indeed, phospholipids and in particular cardiolipin mostly present in the inner mitochondrial membrane, play a crucial role in mitochondria function and oxidative phosphorylation process. We observed that Mstn KO muscle had reduced fat membrane transporter levels (FAT/CD36, FABP3, FATP1 and FATP4) associated with decreased lipid oxidative pathway (citrate synthase and β-HAD activities) and impaired lipogenesis (decreased triglyceride and free fatty acid content), indicating a role of mstn in muscle lipid metabolism. We further analyzed phospholipid classes and fatty acid composition by chromatographic methods in muscle and mitochondrial membranes. Mstn KO mice showed increased levels of saturated and polyunsaturated fatty acids at the expense of monounsaturated fatty acids. We also demonstrated, in this phenotype, a reduction in cardiolipin proportion in mitochondrial membrane versus the proportion of others phospholipids, in relation with a decrease in the expression of phosphatidylglycerolphosphate synthase and cardiolipin synthase, enzymes involved in cardiolipin synthesis. These data illustrate the importance of lipids as a link by which MSTN deficiency can impact mitochondrial bioenergetics in skeletal muscle. (Résumé d'auteur

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The Barth Syndrome Registry: Distinguishing disease characteristics and growth data from a longitudinal study

Roberts

Nixon

Steward

et al. 2012

American J of Med Genetics Pt A

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Barth syndrome (BTHS); MIM accession # 302060) is a rare X‐linked recessive cardioskeletal mitochondrial myopathy with features of cardiomyopathy, neutropenia, and growth abnormalities. The objectives of this study were to further elucidate the natural history, clinical disease presentation, and course, and describe growth characteristics for males with BTHS. Patients with a confirmed genetic diagnosis of BTHS are referred to the BTHS Registry through the Barth Syndrome Foundation, self‐referral, or physician referral. This study is based on data obtained from 73 subjects alive at the time of enrollment that provided self‐reported and/or medical record abstracted data. The mean age at diagnosis of BTHS was 4.04 ± 5.45 years. While the vast majority of subjects reported a history of cardiac dysfunction, nearly 6% denied any history of cardiomyopathy. Although most subjects had only mildly abnormal cardiac function by echocardiography reports, 70% were recognized as having cardiomyopathy in the first year of life and 12% have required cardiac transplantation. Of the 73 enrolled subjects, there have been five deaths. Growth curves were generated demonstrating a shift down for weight, length, and height versus the normative population with late catch up in height for a significant percentage of cases. This data also confirms a significant number of patients with low birth weight, complications in the newborn period, failure to thrive, neutropenia, developmental delay of motor milestones, and mild learning difficulties. However, it is apparent that the disease manifestations are variable, both over time for an individual patient and across the BTHS population. © 2012 Wiley Periodicals, Inc.

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Impaired cardiac reserve and severely diminished skeletal muscle O₂ utilization mediate exercise intolerance in Barth syndrome

Cited by 79 publications

References 44 publications

Endurance Exercise Training in Young Adults with Barth Syndrome: A Pilot Study

Endurance Exercise Training in Young Adults with Barth Syndrome: A Pilot Study

Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

The Barth Syndrome Registry: Distinguishing disease characteristics and growth data from a longitudinal study

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Impaired cardiac reserve and severely diminished skeletal muscle O2 utilization mediate exercise intolerance in Barth syndrome

Cited by 79 publications

References 44 publications

Endurance Exercise Training in Young Adults with Barth Syndrome: A Pilot Study

Endurance Exercise Training in Young Adults with Barth Syndrome: A Pilot Study

Myostatin deficiency is associated with lipidomic abnormalities in skeletal muscles

The Barth Syndrome Registry: Distinguishing disease characteristics and growth data from a longitudinal study

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Impaired cardiac reserve and severely diminished skeletal muscle O₂ utilization mediate exercise intolerance in Barth syndrome