Skeletal muscle metabolism during prolonged exercise in Pompe disease

Objective: Pompe disease (glycogenosis type II) is caused by lysosomal alpha-glucosidase deficiency, which leads to a block in intra-lysosomal glycogen breakdown. In spite of enzyme replacement therapy, Pompe disease continues to be a progressive metabolic myopathy. Considering the health benefits of exercise, it is important in Pompe disease to acquire more information about muscle substrate use during exercise. Methods: Seven adults with Pompe disease were matched to a healthy control group (1:1). We determined (1) peak oxidative capacity (VO2peak) and (2) carbohydrate and fatty acid metabolism during submaximal exercise (33 W) for 1 h, using cycle-ergometer exercise, indirect calorimetry and stable isotopes. Results: In the patients, VO2peak was less than half of average control values; mean difference −1659 mL/min (CI: −2450 to −867, P = 0.001). However, the respiratory exchange ratio increased to >1.0 and lactate levels rose 5-fold in the patients, indicating significant glycolytic flux. In line with this, during submaximal exercise, the rates of oxidation (ROX) of carbohydrates and palmitate were similar between patients and controls (mean difference 0.226 g/min (CI: 0.611 to −0.078, P = 0.318) and mean difference 0.016 μmol/kg/min (CI: 1.287 to −1.255, P = 0.710), respectively). Conclusion: Reflecting muscle weakness and wasting, Pompe disease is associated with markedly reduced maximal exercise capacity. However, glycogenolysis is not impaired in exercise. Unlike in other metabolic myopathies, skeletal muscle substrate use during exercise is normal in Pompe disease rendering exercise less complicated for e.g. medical or recreational purposes

Bezafibrate in skeletal muscle fatty acid oxidation disorders:A randomized clinical trial

OBJECTIVE: To assess whether bezafibrate increases fatty acid oxidation (FAO) and lowers heart rate (HR) during exercise in patients with carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. METHODS: This was a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with CPT II (n = 5) and VLCAD (n = 5) deficiencies. Primary outcome measures were changes in FAO, measured with stable-isotope methodology and indirect calorimetry, and changes in HR during exercise. RESULTS: Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise. CONCLUSION: Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies. These findings indicate that previous in vitro studies suggesting a therapeutic potential for fibrates in disorders of FAO do not translate into clinically meaningful effects in vivo. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies

Pure exercise intolerance and ophthalmoplegia associated with the m.12,294G > A mutation in the MT-TL2 gene: a case report

Abstract Background Pure exercise intolerance associated with exclusive affection of skeletal muscle is a very rare phenotype of patients with mitochondrial myopathy. Moreover, the exercise intolerance in these rare patients is yet not well explored, as most of known cases have not been assessed by objective testing, but only by interview. We report a patient with a mitochondrial DNA (mtDNA) mutation that gives rise to an exclusive myopathy associated with exercise intolerance and ophthalmoplegia. We quantified the patient’s exercise intolerance through detailed exercise testing. Case presentation A 39-year-old man presented with exercise intolerance and chronic progressive external ophthalmoplegia. Sequencing of the entire mtDNA identified a m.12,294G > A mutation in the MT-TL2 gene. The mutation was heteroplasmic in skeletal muscle (75%) while undetectable in blood, urinary sediment, and buccal mucosa as well as in tissues from the patient’s mother. The mutation affected a highly conserved site in the anticodon stem of the mitochondrial transfer RNA Leucine (CUN) molecule and lead to a severe combined respiratory chain defect. Exercise physiological studies in the patient demonstrated a significantly reduced maximal oxygen uptake of 20.4 ml O2 × min−1 × kg−1 (about half of normal) as well as threefold elevated lactate/pyruvate ratios. Conclusion The findings of our study support that the m.12,294G > A mutation is pathogenic. Likely, the mutation arose sporadically in early embryogenesis after differentiation of the mesoderm into muscle progenitor cells, leading to a pure myopathic phenotype