Exercise Intolerance in McArdle Disease: A Role for Cardiac Impairment? A Preliminary Study in Humans and Mice

ABSTRACT 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.