Long-Term Exercise Intervention in Patients with McArdle Disease: Clinical and Aerobic Fitness Benefits

Abstract

Introduction:The long-term effects of exercise in patients with McArdle disease-the paradigm of "exercise intolerance"-are unknown. This is an important question because the severity of the disease frequently increases with time. Purpose: This study aimed to study the effects of a long-term exercise intervention on clinical and fitness-related outcomes in McArdle patients. Methods: Seventeen patients (exercise group: n = 10, 6 male, 38 ± 18 yr; control: n = 7, 4 male, 38 ± 18 yr) participated in a 2-yr unsupervised intervention including moderate-intensity aerobic (cycle-ergometer exercise for 1 h) and resistance (high load-low repetition circuit) training on 5 and 2-3 d•wk −1 , respectively. Patients were assessed at baseline and postintervention. Besides safety, outcomes included clinical severity (e.g., exercise intolerance features) on a 0-3 scale (primary outcome), and aerobic fitness, gross muscle efficiency, and body composition (total/regional fat, muscle, and bone mass; secondary outcomes). Results: The exercise program was safe and resulted in a reduction of 1 point (−1.0; 95% confidence interval, −1.6 to −0.5; P = 0.025) in clinical severity versus the control group, with 60% of participants in the exercise group becoming virtually asymptomatic and with no functional limitation in daily life activities. Compared with controls, the intervention induced significant and large benefits (all P < 0.05) in the workload eliciting the ventilatory threshold (both in absolute (watts, +37%) and relative units (watts per kilogram of total body mass or of lower-limb muscle mass, +44%)), peak oxygen uptake (in milliliters per kilogram per minute, +28%), and peak workload

Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?

“…Indeed, although triheptanoin could replenish Krebs cycle intermediates, this positive effect might be counterbalanced by the presence of damaged mitochondria in the context of a disrupted network of these organelles, thereby suggesting that impairment in glycolytic flux is not the only mechanism underpinning the impaired aerobic capacity of these patients. In the same line, although the peak aerobic capacity of p.R50∗/p.R50∗ mice increases significantly with regular endurance training (for eight weeks, which would be equivalent to ∼one-year duration when translated to ‘human lifespan’), it still remains remarkably lower (∼by 50%) compared to untrained WT mice [ 9 ], which is in accord with findings in patients [ 4 , 36 ].…”

Muscle glycogen unavailability and fat oxidation rate during exercise: Insights from McArdle disease

“…It would be interesting to explore the effect of different training or nutritional interventions on MFO rate and exercise tolerance in these patients in a future analysis. In this regard, there is evidence that regular aerobic exercise can improve the $${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$$ of patients with McArdle disease (Haller et al., 2006; Maté‐Muñoz et al., 2007; Porcelli et al., 2016; Santalla et al., 2022) and previous research has assessed the effects of acute (pre‐exercise) oral administration of branched‐chain amino acids (MacLean et al., 1998) or sucrose (Andersen et al., 2008; Vissing & Haller, 2003b) or of i.v. infusion of glucose (Haller & Lewis, 1991; Haller & Vissing, 2002), triglycerides (Haller & Lewis, 1991), nicotinic acid (a blocker of lipolysis) and a lipid emulsion (soybean oil) (Andersen et al., 2009), as well as fasting during the previous 38 h (Carroll et al., 1979), on the exercise tolerance of these patients.…”

An experiment of nature links muscle glycogen unavailability with very high fat oxidation rates despite low aerobic fitness

“…Studies on patients with McArdle disease form the basis for experiments of nature as highlighted by Joyner et al. (2021), where even a small data set from unusual humans provides unique insights into the role of muscle glycogenolysis in exercise physiology (Joyner et al., 2021; Santalla et al., 2022).…”

“…Historically, patients with McArdle disease have been advised to refrain from exercise because of the risk of rhabdomyolysis, but some patients with an active lifestyle can increase their exercise capacity substantially with favourable metabolic adaptations (Santalla et al., 2022). Also, during acute exercise, the patients experience an augmented fat oxidation (Ørngreen et al., 2009) probably compensating for reduced carbohydrate metabolism.…”

“…The patients suffer from exercise intolerance as described by early fatigue during the start of exercise and during prolonged exercise at high intensities. Studies on patients with McArdle disease form the basis for experiments of nature as highlighted by Joyner et al (2021), where even a small data set from unusual humans provides unique insights into the role of muscle glycogenolysis in exercise physiology (Joyner et al, 2021;Santalla et al, 2022).…”