Cardiopulmonary Exercise Testing and Metabolic Myopathies

Abstract

Skeletal muscle requires a large increase in its ATP production to meet the energy needs of exercise. Normally, most of this increase in ATP is supplied by the aerobic process of oxidative phosphorylation. The main defects in muscle metabolism that interfere with production of ATP are (1) disorders of glycogenolysis and glycolysis, which prevent both carbohydrate entering the tricarboxylic acid cycle and the production of lactic acid; (2) mitochondrial myopathies where the defect is usually within the electron transport chain, reducing the rate of oxidative phosphorylation; and (3) disorders of lipid metabolism. Gas exchange measurements derived from exhaled gas analysis during cardiopulmonary exercise testing can identify defects in muscle metabolism because [Formula: see text]o and [Formula: see text]co are abnormal at the level of the muscle. Cardiopulmonary exercise testing may thus suggest a likely diagnosis and guide additional investigation. Defects in glycogenolysis and glycolysis are identified by a low peak [Formula: see text]o and absence of excess [Formula: see text]co from buffering of lactic acid by bicarbonate. Defects in the electron transport chain also result in low peak [Formula: see text]o, but because there is an overreliance on anaerobic processes, lactic acid accumulation and excess carbon dioxide from buffering occur early during exercise. Defects in lipid metabolism result in only minor abnormalities during cardiopulmonary exercise testing. In defects of glycogenolysis and glycolysis and in mitochondrial myopathies, other features may include an exaggerated cardiovascular response to exercise, a low oxygen-pulse, and excessive ammonia release.

Exercise efficiency impairment in metabolic myopathies

“…We observed non-significant increases in ventilation relative to oxygen consumption (peak V' E /V'O 2 ) in RCDs and relative to carbon dioxide production (V' E /V'CO 2 ; peak and slope values) in both RCD and McArdle patients, in keeping with previous reports 3,11,13,20,21 . The increased work by respiratory muscles in patients with glycogenoses and RCD requires higher oxygen consumption to maintain this activity and may contribute to increase the ∆V'O 2 /∆Work-Rate slope.…”

“…confirmed in all patients by identification of pathogenic mutations in PYGM gene (c.148 C > T/c.148 C > T, n = 5; c.148 C > T/c.1466 C > G, n = 1; c.148 C > T/c.2262delA, n = 1). In this subgroup, the non-ischemic forearm exercise test showed a characteristic flat venous lactate curve with exaggerated increase in blood ammonia 1,5,11 .…”

“…Reduced exercise capacity in metabolic myopathies has a multifactorial origin that may involve 'peripheral'-muscle-mechanisms, such as impairment in mitochondrial ATP regeneration via reduction in substrate delivery to the tricarboxylic acid cycle and decreased oxidative phosphorylation, but also 'central' mechanisms [1][2][3][4][5][6][7][8][9][10][11][12] . Muscle glycogenoses and mitochondrial myopathies are featured by an exaggerated cardiorespiratory response to exercise, including an excessive ventilation and a disproportionate increase in cardiac output relative to muscle oxygen extraction [2][3][4][5][9][10][11][12] . Furthermore, as patients with metabolic myopathies experience exertional symptoms for months or years, the relative contribution of physical deconditioning to their exercise intolerance remains unknown 4,6 .…”

A novel exercise testing algorithm to diagnose mitochondrial myopathy

“…Exercise intolerance is a well‐known clinical feature of mitochondrial myopathy and there has been a longstanding interest in using cardiopulmonary exercise testing (CPET) to support or disprove this diagnosis 3‐5 . An inability to increase systemic arteriovenous oxygen difference (a‐V˙O 2 ) above 10 mg/dL with exercise is sensitive and specific for mitochondrial myopathy in the appropriate clinical setting 4 .…”

Mitochondrial Disease: Advances in Clinical Diagnosis, Management, Therapeutic Development, and Preventative Strategies

“…Cardiopulmonary exercise testing (CPET) is an increasingly useful tool to non-invasively evaluate mitochondrial disease severity, exercise capacity, and to monitor disease progression over time. Characteristic CPET findings in mitochondrial disease include reduced peak work rate and peak exercise oxygen delivery (‘VO 2 max’), elevated respiratory exchange ratio, and early lactic acidosis threshold (31-33).…”