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

E F Diekman,N A W Van Riel,R A J Nievelstein,G Visser,T Takken,M Wardrop,W L Van Der Pol,J P J Schmitz,J A L Jeneson,S M Houten,M De Sain-Van Der Velden,Petras Dzeja

doi:10.1371/journal.pone.0147818

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.

Highlights

The mitochondrial enzyme very-long chain Acyl-CoA dehydrogenase (VLCAD, OMIM 201475) is the first enzyme in the fatty acid oxidation cycle and, as such, a key enzyme in this pathway for mitochondrial energy transduction from fatty acids [1,2]
We demonstrate that prolonged stationary bicycling exercise against a standardized moderate workload in VLCAD deficiency (VLCADD) patients is associated with threefold bigger changes in PCr and Pi concentrations in quadriceps muscle and twofold lower changes in plasma acetylcarnitine levels than in healthy subjects
This result is consistent with the hypothesis that muscle ATP homeostasis during prolonged exercise in VLCADD is compromised

Summary

Introduction

The mitochondrial enzyme very-long chain Acyl-CoA dehydrogenase (VLCAD, OMIM 201475) is the first enzyme in the fatty acid oxidation cycle and, as such, a key enzyme in this pathway for mitochondrial energy transduction from fatty acids [1,2]. In VLCADD, failing myocellular ATP homeostasis during prolonged or intense exercise may result from inhibition of mitochondrial respiration by accumulated incompletely oxidized long-chain fatty acids. Evidence for such an inhibitory mechanism has been found in vitro [11]. An alternative hypothesis for defects in fat oxidation invokes direct damage to the myocellular membrane by high concentrations of incompletely oxidized acylcarnitines that accumulate during prolonged or intense exercise [18] Supportive evidence for this hypothesis has likewise been found in vitro [19,20,21]. Diekman 2015) may argue against the relevance of such a pathophysiological mechanism in vivo

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Conclusion