Evaluation of the Effect of Bezafibrate on Muscle Metabolism During Exercise in Patients With CPTII and VLCAD Deficiency

Background and research aim:

Carnitine palmitoyltransferase II (CPTII) and very-long chain acyl-CoA-dehydrogenase (VLCAD) deficiencies are the two most common inherited disorders of mitochondrial fatty acid oxidation (FAO) in adults, both inherited in an autosomal recessive manner. Mitochondrial FAO plays a pivotal role for maintaining energy homeostasis in situations such as fasting, fever or prolonged exercise that require both glucose sparing and major energy supply. In these situations, a number of tissues such as skeletal muscle, heart, and liver, favour fatty acids as the main source of energy. Long-chain fatty acids (LCFA), that represent the major part of endogenous free fatty acids cannot enter the mitochondrial matrix compartment by simple diffusion, and the transfer of LCFA across the mitochondrial membranes is governed by a multienzymatic system named carnitine palmitoyltransferase (CPT) consisting of two enzymes: CPT I and II. CPT I, a key regulatory step of LCFA oxidation, is located within the outer mitochondrial membrane, while CPT II is appended to the inner face of the inner mitochondrial membrane. CPTs I and II catalyze a single reaction (carnitine + acyl-CoA ⇔ acylcarnitine + CoA~SH) in the forward and reverse directions, respectively. VLCAD is bound to the inner mitochondrial membrane, and catalyses the first step of the long-chain fatty acid β-oxidation spiral (Izai et al., 1992).

Various phenotypes of CPT II and VLACD deficiencies have been described. Severe neonatal or infantile clinical life-threatening symptoms may occur with hypoketotic hypoglycemia, liver failure, and cardiomyopathy during the first months or years of life (Demaugre et al, 1991; Bonnefont et al, 1996; Vianey-Saban et al. 1998; Andresen et al., 1999). Conversely, the "adult" forms of these diseases are more prevalent and have a clinical expression restricted to skeletal muscle. In the latter form, onset most often occurs in teenagers or young adults, and is mainly characterized by recurrent episodes of rhabdomyolysis triggered by prolonged exercise, fasting, cold or fever (DiMauro et al., 1973; Vianey-Saban et al. 1998). The major potential complication is acute renal failure following attacks of rhabdomyolysis.

Studies of fuel utilization in subjects with CPT II and VLCAD deficiencies, with stable isotopes during exercise, have shown that in vivo oxidation of LCFA was severely impaired during prolonged, low-intensity exercise. These findings indicated that residual CPT II and VLCAD activities are sufficient to maintain normal oxidation of fat at rest, but that fat oxidation rate cannot increase above basal level during exercise (Ørngreen et al., 2004; 2005).

Current recommended treatments for long-chain FAO disorders essentially relies on dietary approaches, with restriction of long-chain fat intake along with medium-chain triglyceride supply (MCT oil). A carbohydrate-rich diet also improved exercise tolerance in CPT II-deficient patients, as indicated by lowering of perceived exertion and an increased duration of exercise after such a diet (Ørngreen et al., 2003). More recently, a remarkable improvement of cardiac and muscular symptoms occurred in three children with VLCAD deficiency, after dietary supplementation with a seven-carbon medium chain fatty acid (triheptanoïn). The mechanism underlying this effect is believed to involve the production of C5 ketone bodies and propionyl-CoA, which allows for replenishment of the pool of catalytic intermediates for the citric acid cycle (Roe et al., 2002). This promising approach is still under evaluation and marked digestive side effects could restrict its indication towards the more severe form of FAO defects. Pharmacological approaches are mainly carnitine supplementation in order to provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines. However, the role of carnitine supplements in FAO defects remains controversial and of unproven value due to the absence of controlled trials.