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

KEY POINTS: Physically active McArdle patients shown an exceptional fat oxidation capacity. Maximal fat oxidation rate occurs near-maximal exercise capacity in these patients. McArdle patients' exercise tolerance might rely on maximal fat oxidation rate capacity. Hyperpnoea patients might, however, cloud substrate oxidation measurements in some patients. An animal model revealed overall no higher molecular markers of lipid transport/metabolism.

ABSTRACT: Carbohydrate availability affects fat metabolism during exercise; however, the effects of complete muscle glycogen unavailability on maximal fat oxidation (MFO) rate remain unknown. Our purpose was to examine MFO rate in patients with McArdle disease-an inherited condition caused by complete blockade of muscle glycogen metabolism-compared to healthy controls. Nine patients (3 women, 36 ± 12yrs) and 12 healthy controls (4 women, 40 ± 13yrs) were studied. Several molecular markers of lipid transport/metabolism were also determined in skeletal muscle (gastrocnemius) and white adipose tissue of McArdle (Pygm p.50R*/p.50R*) and wild-type mice. Peak oxygen uptake (VO2 peak), MFO rate, the exercise intensity eliciting MFO rate (FATmax), and the MFO rate-associated workload were determined by indirect calorimetry during an incremental cycle-ergometer test. Despite having a much lower V̇O2 peak (24.7 ± 4 vs. 42.5  ±  11.4 ml·kg-1 ·min-1 , respectively; P < 0.0001), patients showed considerably higher values of MFO rate (0.53 ± 0.12 vs. 0.33 ± 0.10 g·min-1 , P = 0.001), FATmax (94.4 ± 7.2 vs. 41.3 ± 9.1 % of V̇O2 peak, P < 0.0001) and MFO rate-associated workload (1.33 ± 0.35 vs. 0.81 ± 0.54 watts·kg-1 , P = 0.020) than controls. No between-group differences were found overall in molecular markers of lipid transport/metabolism in mice. In summary, patients with McArdle disease show an exceptionally high MFO rate, which they attained at near-maximal exercise capacity. Pending more mechanistic explanations, these findings support the influence of glycogen availability on MFO rate and suggest that these patients develop a unique fat oxidation capacity, possibly as an adaptation to compensate for the inherited blockade in glycogen metabolism, and point to MFO rate as a potential limiting factor of exercise tolerance in this disease. Abstract figure legend McArdle disease is caused by inherited blockade of glycogen breakdown in skeletal muscle fibers, with subsequent intolerance to most exercise tasks as well as a substantial impairment of peak aerobic capacity. This study supports that the exercise capacity of these patients is mainly sustained by fat oxidation, with active patients showing an exceptional maximal fat oxidation rate (similar in fact to athletes) during endurance exercise, possibly as an adaptation to muscle glycogen unavailability. On the other hand, data in the (untrained) mouse model of the disease revealed overall no major differences at baseline in molecular markers of lipid transport/metabolism, compared with wild-type mice.

ABBREVIATIONS: AMPK, AMP-activated protein kinase; CD36, transmembrane glycoprotein cluster of differentiation 36; HADH, 3-hydroxyacyl-CoA dehydrogenase; HSL, hormone-sensitive lipase (total or phosphorylated); MFO, maximum fat oxidation; NS, 'no significant' (for between-group comparisons). pAMPK, phosphorylated AMPK; pATGL, phosphorylated adipose triglyceride lipase; Plin5, perilipin 5; VO2 peak, peak oxygen uptake. Data presented as mean (SD). This article is protected by copyright. All rights reserved.