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.

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long‐chain acyl‐CoA dehydrogenase‐deficient mice

“…In light of the recent findings in VLCAD patients [38], it is conceivable to imagine a similar modulating effect of medium-chain fatty acids also in humans. Since no long-term studies on the effects of mediumchain fatty acids have been performed to date, the impact of the metabolic/ morphologic adaptation on the muscular clinical phenotype is unknown yet.…”

“…Interestingly, long-term supplementation with even medium-chain fatty acids seems to inhibit the progressive metabolic and the very likely morphologic transition of muscle fibers in VLCAD À/À mice. Indeed, mathematical modeling of oxidative ATP metabolism in quadriceps muscle from VLCAD subjects performing 45 min of bicycle exercise also suggests a switch in muscle fiber composition in VLCAD patients from oxidative to glycolytic [38] metabolism but without mentioning the concomitant upregulation of the mFA-SII/lipoic acid biosynthesis pathways. We, therefore, suppose in line with the observation in untreated mutants that triheptanoin drives the metabolic and likely a morphologic transition of muscle fibers toward glycolytic species.…”

Triheptanoin versus trioctanoin for long‐chain fatty acid oxidation disorders: a double blinded, randomized controlled trial

“…The 31 P–phosphocreatine recovery study was designed to indirectly evaluate muscle ATP synthesis, but the acute nature of our testing protocol with resistance exercise for only 2 min may have been of insufficient duration or exercise type to fully engage muscle FAO and may have been inadequate to detect significant differences between treatment groups. Indeed, a recent published study evaluating PCr recovery rates among subjects with VLCAD deficiency and controls after 45 min of exercise observed that while PCr depletion was greater among subjects with VLCAD, the rate of recovery was similar to controls (Diekman et al 2016). These data suggest that the rate of PCr recovery is normal among subjects with a LC-FAOD and may not be expected to improve with treatment.…”

“…At OHSU site, the coil was placed on the tibialis anterior and the subject performed ankle-flexion exercise. The 31 P spectra were acquired continuously every 1.1 s during the three phases of the protocol (Diekman et al 2016). Not all subjects completed the PCr recovery measurement and children under age 16 did not complete this outcome measure.…”

A low-cost Mr compatible ergometer to assess post-exercise phosphocreatine recovery kinetics

“…In low intensity exercise regimes, PCr recovery follows monoexponential kinetics [5, 18], which implies a linear steady-state relationship of oxidative ATP synthesis to PCr depletion, and vice versa [19–21]. 31 P-MRS data interpretation during voluntary exercise (as opposed to during recovery of PCr following exercise) is significantly more involved, and requires several assumptions about motor unit recruitment with the particular exercise protocol and workload used [22]. …”