Altered Energetics of Exercise Explain Risk of Rhabdomyolysis in Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

Abstract

Rhabdomyolysis is common in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and other metabolic myopathies, but its pathogenic basis is poorly understood. Here, we show that prolonged bicycling exercise against a standardized moderate workload in VLCADD patients is associated with threefold bigger changes in phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations in quadriceps muscle and twofold lower changes in plasma acetyl-carnitine levels than in healthy subjects. This result is consistent with the hypothesis that muscle ATP homeostasis during exercise is compromised in VLCADD. However, the measured rates of PCr and Pi recovery post-exercise showed that the mitochondrial capacity for ATP synthesis in VLCADD muscle was normal. Mathematical modeling of oxidative ATP metabolism in muscle composed of three different fiber types indicated that the observed altered energy balance during submaximal exercise in VLCADD patients may be explained by a slow-to-fast shift in quadriceps fiber-type composition corresponding to 30% of the slow-twitch fiber-type pool in healthy quadriceps muscle. This study demonstrates for the first time that quadriceps energy balance during exercise in VLCADD patients is altered but not because of failing mitochondrial function. Our findings provide new clues to understanding the risk of rhabdomyolysis following exercise in human VLCADD.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1

(A) Maximal workload of symptomatic (black squares) and asymptomatic (open squares) VLCADD patients and controls. (B) in symptomatic (black squares) and asymptomatic (open squares) VLCADD patients. (C) Fatty acid oxidation in mg/kg body mass/min in VLCADD patients and controls. Error bars indicate ± SEM. *P

Fig 2

(A) Glucose, (B) lactate and(C) acetylcarnitine at t = 0 (rest), t = 1 (directly after exercise) and t = 2 (3 hours after exercise) in symptomatic VLCADD patients and controls. Error bars indicate mean ± SEM, *P

Fig 3

(A) 31P NMR spectra acquired from the lateral head of the quadriceps muscle of the right leg of a VLCAD deficient patient versus a healthy control subject during 5 min of bicycling exercise at a workload equivalent to FATMAX in each subject. (B) Each spectrum represents the sum of the FIDs collected after 60 s of exercise. FIDs were apodized in the time domain using a 10-Hz low-pass filter prior to Fourier transform and phasing. Peak assignments: Pi inorganic phosphate, PCr phosphocreatine, ATP adenosine triphosphate (gamma, alpha and beta resonances, respectively). (C) Average change in PCr and Pi during exercise (in mM) in healthy control subjects versus symptomatic and asymptomatic VLCAD deficient patients. Error bars indicate mean ± SEM, *P<0.05.

Fig 4. pH dynamics during exercise and first minutes of recovery.

The error bars show the variance in the data from AMARES fitting of the MR spectra (see Methods section). (A) Healthy controls. (B-D) VLCADD patients. Solid red lines show the fit of linear or monoexponential functions to the data; blue lines show the 95% confidence interval of the fit.

Fig 5. Pi dynamics during exercise and the first minutes of recovery rates.

The error bars show the variance in the data from AMARES fitting of the MR spectra (see Methods section). (A) Healthy controls. (B-D) VLCADD patients. Solid red lines show the fit of a monoexponential function to the data; blue lines show the 95% confidence interval of the fit.