Exercise Intolerance in McArdle Disease: A Role for Cardiac Impairment? A Preliminary Study in Humans and Mice
Year: 2024
Type: article
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.
Authors: ALEJANDRO SANTOS-LOZANO, ARACELI BORAITA, PEDRO L. VALENZUELA, ALFREDO SANTALLA, MÓNICA VILLARREAL-SALAZAR, ASUNCIÓN BUSTOS, LIDIA B. ALEJO, DAVID BARRANCO-GIL, DANIELA MILLÁN-PARLANTI, SUSANA LÓPEZ-ORTIZ, SAúL PEÑÍN-GRANDES, JOSé NARANJO ORELLANA, CARMEN FIUZA-LUCES, BEATRIZ G. GáLVEZ, MIGUEL ÁNGEL GARCÍA-FERNáNDEZ, TOMÀS PINÓS, ALEJANDRO LUCIA
Institutions: Universidad Europea Miguel de Cervantes, Research Institute Hospital 12 de Octubre, Universidad Europea de Madrid, Universidad de Alcalá, Universidad Europea de Canarias, Universidad Pablo de Olavide, Universitat Autònoma de Barcelona, Vall d'Hebron Institut de Recerca, Centre for Biomedical Network Research on Rare Diseases, Universidad Complutense de Madrid
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4401715226