Karen Lindhardt Madsen

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.

Exercise intolerance in Glycogen Storage Disease Type III: Weakness or energy deficiency?

Myopathic symptoms in Glycogen Storage Disease Type IIIa (GSD IIIa) are generally ascribed to the muscle wasting that these patients suffer in adult life, but an inability to debranch glycogen likely also has an impact on muscle energy metabolism. We hypothesized that patients with GSD IIIa can experience exercise intolerance due to insufficient carbohydrate oxidation in skeletal muscle. Six patients aged 17-36-years were studied. We determined VO 2peak (peak oxygen consumption), the response to forearm exercise, and the metabolic and cardiovascular responses to cycle exercise at 70% of VO 2peak with either a saline or a glucose infusion. VO 2peak was below normal. Glucose improved the work capacity by lowering the heart rate, and increasing the peak work rate by 30% (108 W with glucose vs. 83 W with placebo, p=0.018). The block in muscle glycogenolytic capacity, combined with the liver involvement caused exercise intolerance with dynamic skeletal muscle symptoms (excessive fatigue and muscle pain), and hypoglycemia in 4 subjects. In this study we combined anaerobic and aerobic exercise to systematically study skeletal muscle metabolism and exercise tolerance in patients with GSD IIIa. Exercise capacity was significantly reduced, and our results indicate that this was due to a block in muscle glycogenolytic capacity. Our findings suggest that the general classification of GSD III as a glycogenosis characterized by fixed symptoms related to muscle wasting should be modified to include dynamic exercise-related symptoms of muscle fatigue. A proportion of the skeletal muscle symptoms in GSD IIIa, i.e. weakness and fatigue, may be related to insufficient energy production in muscle.

Training improves oxidative capacity, but not function, in spinal muscular atrophy type III

In this study we investigated the effect of 12 weeks of cycle ergometer training in patients with spinal muscular atrophy type III (SMA III), a hereditary motor neuron disease with progressive muscle weakness and atrophy.

Fat and carbohydrate metabolism during exercise in late-onset Pompe disease

Pompe disease is caused by absence of the lysosomal enzyme acid alpha-glucosidase. It is generally assumed that intra-lysosomal hydrolysis of glycogen does not contribute to skeletal muscle energy production during exercise. However, this hypothesis has never been tested in vivo during exercise. We examined the metabolic response to exercise in patients with late-onset Pompe disease, in order to determine if a defect in energy metabolism may play a role in the pathogenesis of Pompe disease. We studied six adult patients with Pompe disease and 10 healthy subjects. The participants underwent ischemic forearm exercise testing, and peak work capacity was determined. Fat and carbohydrate metabolism during cycle exercise was examined with a combination of indirect calorimetry and stable isotope methodology. Finally, the effects of an IV glucose infusion on heart rate, ratings of perceived exertion, and work capacity during exercise were determined. We found that peak oxidative capacity was reduced in the patients to 17.6 vs. 38.8 ml kg(-1) min(-1) in healthy subjects (p = 0.002). There were no differences in the rate of appearance and rate of oxidation of palmitate, or total fat and carbohydrate oxidation, between the patients and the healthy subjects. None of the subjects improved exercise tolerance by IV glucose infusion. In conclusion, peak oxidative capacity is reduced in Pompe disease. However, skeletal muscle fat and carbohydrate use during exercise was normal. The results indicate that a reduced exercise capacity is caused by muscle weakness and wasting, rather than by an impaired skeletal muscle glycogenolytic capacity. Thus, it appears that acid alpha-glucosidase does not play a significant role in the production of energy in skeletal muscle during exercise.

Creatine kinase response to high-intensity aerobic exercise in adult-onset muscular dystrophy

We investigated the effect of high‐intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies.

Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III

Objective: Glycogen storage disease type IIIa (GSDIIIa) is classically regarded as a glycogenosis with fixed weakness, but we hypothesized that exercise intolerance in GSDIIIa is related to muscle energy failure and that oral fructose ingestion could improve exercise tolerance in this metabolic myopathy. Methods: We challenged metabolism with cycle-ergometer exercise and measured substrate turnover and oxidation rates using stable isotope methodology and indirect calorimetry in 3 patients and 6 age-matched controls on 1 day, and examined the effect of fructose ingestion on exercise tolerance in the patients on another day. Results: Total fatty acid oxidation rates during exercise were higher in patients than controls, 32.1 (SE 1.2) vs 20.7 (SE 0.5; range 15.8–29.3) μmol/kg/min (p = 0.048), and oxidation of carbohydrates was lower in patients, 1.0 (SE 5.4) vs 38.4 (SE 8.0; range 23.0–77.1) μmol/kg/min (p = 0.024). Fructose ingestion improved exercise tolerance in the patients. Conclusion: Similar to patients with McArdle disease, in whom muscle glycogenolysis is also impaired, GSDIIIa is associated with a reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation, and fructose ingestion improves exercise tolerance. Our results indicate that GSDIIIa should not only be viewed as a glycogenosis with fixed skeletal muscle weakness, but should also be considered among the glycogenoses presenting with exercise-related dynamic symptoms caused by muscular energy deficiency. Classification of evidence: This study provides Class IV evidence that ingestion of fructose improves exercise tolerance in patients with GSDIIIa.

Patients With Medium-Chain Acyl–Coenzyme A Dehydrogenase Deficiency Have Impaired Oxidation of Fat During Exercise but No Effect of l-Carnitine Supplementation

BACKGROUND It is not clear to what extent skeletal muscle is affected in patients with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD). l-Carnitine is commonly used as a supplement in patients with MCADD, although its beneficial effect has not been verified. DESIGN We investigated (1) fuel utilization during prolonged low-intensity exercise in patients with MCADD and (2) the influence of 4 weeks of oral l-carnitine supplementation on fuel utilization during exercise. METHODS Four asymptomatic patients with MCADD and 11 untrained, healthy, age- and sex-matched control subjects were included. The subjects performed a 1-hour cycling test at a constant workload corresponding to 55% of Vo2max, while fat and carbohydrate metabolism was assessed, using the stable isotope technique and indirect calorimetry. The patients ingested 100 mg/kg/d of l-carnitine for 4 weeks, after which the cycling tests were repeated. RESULTS At rest, palmitate oxidation and total fatty acid oxidation (FAO) rates were similar in patients and healthy control subjects. During constant workload cycling, palmitate oxidation and FAO rates increased in both groups, but increased 2 times as much in healthy control subjects as in patients (P = .007). Palmitate oxidation and FAO rates were unchanged by the l-carnitine supplementation. CONCLUSION Our results indicate that patients with MCADD have an impaired ability to increase FAO during exercise but less so than that observed in patients with a number of other disorders of fat oxidation, which explains the milder skeletal muscle phenotype in MCADD. The use of carnitine supplementation in MCADD cannot be supported by the present findings.

Muscle glycogen synthesis and breakdown are both impaired in glycogenin-1 deficiency

Objective: To study fat and carbohydrate metabolism during exercise in patients with glycogenin-1 (GYG1) deficiency, and to study whether IV glucose supplementation can alleviate exercise intolerance in these patients. Methods: This is a case-control study with 4 patients with GYG1 deficiency and 4 healthy controls. Patients performed 1 hour of cycling at 50% of their maximal workload capacity, while controls cycled at the same absolute workloads as patients. Heart rate was measured continuously, and production and utilization of fat and glucose was assessed by stable isotope technique. The following day, patients repeated the exercise, this time receiving an IV 10% glucose supplement. Results: Glucose utilization during exercise was similar in patients and controls, while palmitate utilization was greater in patients compared to controls. However, exercise-induced increases in lactate were attenuated to about half normal in patients. This was also the case during a handgrip exercise test. Glucose infusion improved exercise tolerance in patients, and lowered heart rate by on average 11 beats per minute during exercise. Conclusions: The findings suggest that patients with GYG1 deficiency not only have abnormal formation of glycogen, but also have impaired muscle glycogenolysis, as suggested by impaired lactate production during exercise and improved exercise tolerance with glucose infusion.

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.

L-carnitine improves skeletal muscle fat oxidation in Primary Carnitine Deficiency.

Context Primary carnitine deficiency (PCD) is an inborn error of fatty acid metabolism. Patients with PCD are risk for sudden heart failure upon fasting or illness if they are not treated with daily l-carnitine. Objective To investigate energy metabolism during exercise in patients with PCD with and without l-carnitine treatment. Design Interventional study. Setting Hospital exercise laboratories and department of cardiology. Participants Eight adults with PCD who were homozygous for the c.95A>G (p.N32S) mutation and 10 healthy age- and sex-matched controls. Intervention Four-day pause in l-carnitine treatment. Main outcome measures Total fatty acid and palmitate oxidation rates during 1-hour submaximal cycle ergometer exercise assessed with stable isotope method (U13C-palmitate and 2H2-d-glucose) and indirect calorimetry with and without l-carnitine. Results Total fatty acid oxidation rate was higher in patients with l-carnitine treatment during exercise than without treatment [12.3 (SD, 3.7) vs 8.5 (SD, 4.6) µmol × kg-1 × min-1; P = 0.008]. However, the fatty acid oxidation rate was still lower in patients treated with l-carnitine than in the healthy controls [29.5 (SD, 10.1) µmol × kg-1 × min-1; P < 0.001] and in the l-carnitine group without treatment it was less than one third of that in the healthy controls (P < 0.001). In line with this, the palmitate oxidation rates during exercise were lower in the no-treatment period [144 (SD, 66) µmol × kg-1 × min-1] than during treatment [204 (SD, 84) µmol × kg-1 × min-1; P = 0.004) . Conclusions The results indicate that patients with PCD have limited fat oxidation during exercise. l-Carnitine treatment in asymptomatic patients with PCD may not only prevent cardiac complications but also boost skeletal muscle fat metabolism during exercise.