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

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 the MFO rate in patients with McArdle disease, comprising an inherited condition caused by complete blockade of muscle glycogen metabolism, compared to healthy controls. Nine patients (three women, aged 36 ± 12 years) and 12 healthy controls (four women, aged 40 ± 13 years) 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 male mice. Peak oxygen uptake (trueV̇normalO2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$), 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 trueV̇normalO2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ (24.7 ± 4 vs. 42.5 ± 11.4 mL kg−1 min−1, respectively; P < 0.0001), patients showed considerably higher values for the MFO rate (0.53 ± 0.12 vs. 0.33 ± 0.10 g min−1, P = 0.001), and for the FATmax (94.4 ± 7.2 vs. 41.3 ± 9.1 % of trueV̇normalO2peak${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$, P < 0.0001) and MFO rate‐associated workload (1.33 ± 0.35 vs. 0.81 ± 0.54 W 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. Key points Physically active McArdle patients show 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 might cloud substrate oxidation measurements in some patients. An animal model revealed overall no higher molecular markers of lipid transport/metabolism.

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

“…The study by Rodriguez‐Lopez et al. (2022) provides important additional observations to this understanding by showing that the patients with McArdle disease demonstrate very high fat oxidation rates at exercise intensities close to their maximal. The patients reached a maximal fat oxidation rate of 0.53 g min −1 , which was around 60% higher than the healthy controls (0.33 g min −1 ) included in the study.…”

“…The study by Rodriguez‐Lopez et al. (2022) clearly demonstrates that, despite a low aerobic capacity, patients with McArdle disease possess a very high maximal fat oxidation rate. To understand this phenomenon better, Rodriguez‐Lopez et al.…”

“…To understand this phenomenon better, Rodriguez‐Lopez et al. (2022) included assessments of key regulatory proteins in fat metabolism in muscles from a validated mouse model of McArdle disease and found no increase in a fatty acid transporter protein (CD36) or in lipolytic capacity (hormone‐sensitive lipase), and even found a decreased mitochondrial capacity (as suggested by lower levels of 3‐hydroxyacyl‐CoA dehydrogenase). Therefore, the results from the study by Rodriguez‐Lopez et al.…”

“…Therefore, the results from the study by Rodriguez‐Lopez et al. (2022) pave the way for investigating other potential regulatory steps in fat metabolism, such as carnitine palmitoyl transferase I and the mobilization of fatty acids from intramuscular lipid droplets to mitochondria, which is probably influenced by lipid droplet–mitochondrial interactivity and regulatory proteins as perilipins.…”

“…2022) included assessments of key regulatory proteins in fat metabolism in muscles from a validated mouse model of McArdle disease and found no increase in a fatty acid transporter protein (CD36) or in lipolytic capacity (hormone-sensitive lipase), and even found a decreased mitochondrial capacity (as suggested by lower levels of 3-hydroxyacyl-CoA dehydrogenase). Therefore, the results from the study by Rodriguez-Lopez et al (2022) pave the way for investigating other potential regulatory steps in fat metabolism, such as carnitine palmitoyl transferase I and the mobilization of fatty acids from intramuscular lipid droplets to mitochondria, which is probably influenced by lipid droplet-mitochondrial interactivity and regulatory proteins as perilipins. The results conform with findings from healthy individuals, where a low muscle glycogen level is strongly associated with a high fat oxidation rate (Arkinstall et al, 2004).…”