Nicolai Preisler

Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease)

Objective: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage in SBMA also occurs independently of motor neuron damage. Methods: Eight patients with SBMA engaged in regular cycling exercise for 12 weeks. Maximum oxygen uptake (Vo2max), maximal work capacity (Wmax), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training. Results: Wmax increased by 18%, and CS activity increased by 35%. There was no significant change in Vo2max or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. Conclusions: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma creatine kinase and muscle regeneration indicate a primary myopathic affection, which, in parallel with the motor neuron deficiency, may attenuate the response to exercise training in patients with SBMA.

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.

Fat metabolism during exercise in patients with McArdle disease

Objective: It is known that muscle phosphorylase deficiency restricts carbohydrate utilization, but the implications for muscle fat metabolism have not been studied. We questioned whether patients with McArdle disease can compensate for the blocked muscle glycogen breakdown by enhancing fat oxidation during exercise. Methods: We studied total fat oxidation by indirect calorimetry and palmitate turnover by stable isotope methodology in 11 patients with McArdle disease and 11 healthy controls. Cycle exercise at a constant workload of 50% to 60% of maximal oxygen uptake capacity was used to evaluate fatty acid oxidation (FAO) in the patients. Healthy controls were exercised at the same absolute workload. Results: We found that palmitate oxidation and disposal, total fat oxidation, and plasma levels of palmitate and total free fatty acids (FFAs) were significantly higher, whereas total carbohydrate oxidation was lower, during exercise in patients with McArdle disease vs healthy controls. We found augmented fat oxidation with the onset of a second wind, but further increases in FFA availability, as exercise continued, did not result in further increases in FAO. Conclusion: These results indicate that patients with McArdle disease have exaggerated fat oxidation during prolonged, low-intensity exercise and that increased fat oxidation may be an important mechanism of the spontaneous second wind. The fact that increasing availability of free fatty acids with more prolonged exercise did not increase fatty acid oxidation suggests that blocked glycogenolysis may limit the capacity of fat oxidation to compensate for the energy deficit in McArdle disease. BMI = body mass index; bpm = beats per minute; CHO = carbohydrate oxidation; FAO = fatty acid oxidation; FFA = free fatty acid; Ra = rate of appearance; Rd = rate of disappearance; RER = respiratory exchange rate; Rox = rate of oxidation; TAG = triacylglycerol; TCA = tricarboxylic acid; VO2= oxygen consumption; VO2max = maximal oxygen uptake capacity.

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 Phosphoglucomutase Type 1 Deficiency

CONTEXT Phosphoglucomutase type 1 (PGM1) deficiency is a rare metabolic myopathy in which symptoms are provoked by exercise. OBJECTIVE Because the metabolic block is proximal to the entry of glucose into the glycolytic pathway, we hypothesized that iv glucose could improve the exercise intolerance experienced by the patient. DESIGN This was an experimental intervention study. SETTING The study was conducted in an exercise laboratory. SUBJECTS Subjects were a 37-year-old man with genetically and biochemically verified PGM1 deficiency and 6 healthy subjects. INTERVENTIONS Cycle ergometer, peak and submaximal exercise (70% of peak oxygen consumption), and exercise with an iv glucose infusion tests were performed. MAIN OUTCOME MEASURES Peak work capacity and substrate metabolism during submaximal exercise with and without an iv glucose infusion were measured. RESULTS Peak work capacity in the patient was normal, as were increases in plasma lactate during peak and submaximal exercise. However, the heart rate decreased 11 beats minute⁻¹, the peak work rate increased 12.5%, and exercise was rated as being easier with glucose infusion in the patient. These results were in contrast to those in the control group, in whom no improvements occurred. In addition, the patient tended to become hypoglycemic during submaximal exercise. CONCLUSIONS This report characterizes PGM1 deficiency as a mild metabolic myopathy that has dynamic exercise-related symptoms in common with McArdle disease but no second wind phenomenon, thus suggesting that the condition clinically resembles other partial enzymatic defects of glycolysis. However, with glucose infusion, the heart rate decreased 11 beats min⁻¹, the peak work rate increased 12.5%, and exercise was considered easier by the patient.

Muscle phosphorylase kinase deficiency: A neutral metabolic variant or a disease?

Objective: To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD). Methods: Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment. Both patients had increased glycogen levels in muscle and PHK activity <11% of normal. Two novel pathogenic nonsense mutations were found in the PHKA1 gene. The metabolic response to anaerobic forearm exercise and aerobic cycle exercise was studied in the patients and 5 healthy subjects. Results: Ischemic exercise showed a normal 5-fold increase in plasma lactate (peak 5.7 and 6.9 mmol/L) but an exaggerated 5-fold increase in ammonia (peak 197 and 171 μmol/L; control peak range 60–113 μmol/L). An incremental exercise test to exhaustion revealed a blunted lactate response (5.4 and 4.8 mmol/L) vs that for control subjects (9.6 mmol/L; range 7.1–14.3 mmol/L). Fat and carbohydrate oxidation rates at 70% of peak oxygen consumption were normal. None of the patients developed a second wind phenomenon or improved their work capacity with an IV glucose infusion. Conclusion: Our findings demonstrate that muscle PHK deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle glycogenolysis, raised CK levels, and glycogen accumulation in muscle. The relative preservation of glycogenolysis is probably explained by an alternative activation of myophosphorylase by AMP and Pi at high exercise intensities. Neurology® 2012;78:265–268

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.

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.

Aerobic training in persons who have recovered from juvenile dermatomyositis

A recent study has shown that 36 persons who had recovered from juvenile dermatomyositis (JDM) have on average an 18% decrease in maximal oxygen uptake. The objective of this study was to investigate the effect of a 12-week aerobic training program in this group, and assess whether aerobic training can normalize aerobic capacity to the expected level for age and gender. The patients participating in the study, one male and nine females (16-42 years of age), were in remission from JDM, defined as no clinical or biochemical evidence of disease activity and no medical treatment for 1 year. The patients had a median disease duration of 3.4 years (1.4-10.3), a median treatment duration of 2.4 years (0.4-9.3) and a median duration of remission of 7.0 years (1.2-30.0). Patients trained at home on a cycle ergometer for 12 weeks at a heart rate interval corresponding to 65% of their maximal oxygen uptake (VO(2max)). VO(2max) and maximal workload (W(max)) were determined before and after the 12-week training period through an incremental cycling test to exhaustion. The patients served as their own controls. Eight patients with JDM in remission completed the 12-week exercise program; one patient completed 9 weeks out of the 12-week program and one dropped out of the study. Training increased VO(2max) and W(max) by 26% and 30% (P < 0.001). Creatine kinase (CK) levels were normal pre-training and did not change with training, reflecting no muscle damage. We also found that at a given workload, heart rate was lowered significantly after the 12-week training period, indicating an improvement in cardiovascular fitness. This study shows that 12 weeks of moderate-intensity aerobic training is an effective and safe method to increase oxidative capacity and fitness in persons who have recovered from JDM. The results indicate that the low oxidative capacity in JDM patients in remission is reversible and can be improved. Thus, we recommend frequent aerobic training to be incorporated into supervised physiotherapy sessions in the treatment of JDM patients in remission.