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Exercise Intolerance in McArdle Disease: A Role for Cardiac Impairment? A Preliminary Study in Humans and Mice
Alejandro Santos-Lozano, Araceli Boraita, Pedro L Valenzuela
1Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, SPAIN.
Insights
McArdle disease patients show preserved cardiac function despite exercise intolerance. However, impaired cardiac contractility may be linked to the "second wind" phenomenon, warranting further investigation.
Area of Science:
- Cardiology
- Exercise Physiology
- Rare Diseases
Background:
- McArdle disease is characterized by exercise intolerance due to myophosphorylase deficiency.
- The impact of McArdle disease on cardiac function remains largely undetermined.
Purpose of the Study:
- To investigate cardiac structure and function in patients with McArdle disease during exercise.
- To explore potential cardiac compensation mechanisms in McArdle disease.
Main Methods:
- Echocardiography (including GLS) and ECG were used to assess cardiac function in McArdle patients and controls during exercise.
- Histological and molecular analyses were performed on human heart biopsies and mouse models.
Main Results:
- McArdle patients exhibited exercise intolerance and a decrease in GLS during exercise, particularly during the 'second wind' phenomenon.
- No significant differences in overall cardiac structure or function were observed between patients and controls.
- Human hearts express multiple glycogen phosphorylase isoforms, suggesting potential compensation for myophosphorylase deficiency.
Conclusions:
- Cardiac structure and function appear preserved in McArdle disease.
- The association between impaired cardiac contractility and the 'second wind' phenomenon requires further research.
Introduction:
Whether cardiac impairment can be fully discarded in McArdle disease-the paradigm of "exercise intolerance," caused by inherited deficiency of the skeletal muscle-specific glycogen phosphorylase isoform ("myophosphorylase")-remains to be determined.
Methods:
Eight patients with McArdle disease and seven age/sex-matched controls performed a 15-min moderate, constant-load cycle-ergometer exercise bout followed by a maximal ramp test. Electrocardiographic and two-dimensional transthoracic (for cardiac dimension's assessment) and speckle tracking (for left ventricular global longitudinal strain (GLS) assessments) echocardiographic evaluations were performed at baseline. Electrocardiographic and GLS assessments were also performed during constant-load exercise and immediately upon maximal exertion. Four human heart biopsies were obtained in individuals without McArdle disease, and in-depth histological/molecular analyses were performed in McArdle and wild-type mouse hearts.
Results:
Exercise intolerance was confirmed in patients ("second wind" during constant-load exercise, -55% peak power output vs controls). As opposed to controls, patients showed a decrease in GLS during constant-load exercise, especially upon second wind occurrence, but with no other between-group difference in cardiac structure/function. Human cardiac biopsies showed that all three glycogen phosphorylase-myophosphorylase, but also liver and especially brain-isoforms are expressed in the normal adult heart, thereby theoretically compensating for eventual myophosphorylase deficiency. No overall histological (including glycogen depots), cytoskeleton, metabolic, or mitochondrial (morphology/network/distribution) differences were found between McArdle and wild-type mouse hearts, except for lower levels of pyruvate kinase M2 and translocase of outer-membrane 20-kDa subunit in the former.
Conclusions:
This study provides preliminary evidence that cardiac structure and function seem to be preserved in patients with McArdle disease. However, the role for an impaired cardiac contractility associated with the second wind phenomenon should be further explored.
