No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease and healthy controls: A randomized placebo-controlled cross-over study.

Patients with glycogen storage disease type V (GSDV), also known as McArdle disease, have blocked glycogen breakdown due to myophosphorylase deficiency, leading to exercise intolerance, muscle pain, and risk of muscle damage. Blood-derived ketone bodies (KBs) constitute an alternative energy source that could fuel the muscle independent of glycogenolysis. However, except for long-time fasting or ketogenic dieting, KBs are present in low quantities. This led us to explore the effects of a drink containing exogenously produced KBs in the form of D-ß-hydroxybutyrate esters (KE) on exercise capacity and metabolism in patients with GSDV. Eight GSDV patients and four healthy controls (HC) were included in this placebo-controlled, cross-over study where subjects were randomized to receive a KE drink with 395 mgKE/kg or placebo drink on two separate days 25 min before a submaximal cycle exercise test. The primary outcome was exercise capacity as indicated by heart rate response (HR) to exercise. Secondary outcomes included perceived exertion (PE) and measures of KB, carbohydrate, and fat metabolism during exercise. In GSDV, the KE drink vs. placebo increased plasma KBs and KB oxidation (p ≤ 0.0001) but did not improve exercise capacity as judged from HR (p = 0.120) and PE (p = 0.109). In addition, the KE drink lowered plasma glucose, free fatty acids, and lowered lipolytic rate and glucose rate of appearance compared with placebo. Similar results were found in the HC group. The present study indicates that an increase in KB oxidation by oral KE supplementation does not improve exercise capacity in GSDV possibly because of KB-induced inhibition of lipolysis and liver glucose output. Thus, oral KE supplementation alone cannot be recommended as a treatment option for patients with GSDV.

No effect of resveratrol on fatty acid oxidation or exercise capacity in patients with fatty acid oxidation disorders: A randomized clinical cross-over trial.

The objective was to investigate whether resveratrol (RSV) can improve exercise capacity in patients with fatty acid oxidation (FAO) disorders. The study was a randomized, double-blind, cross-over trial. Nine patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency or carnitine palmitoyl transferase (CPT) II deficiency were randomized to receive either 8 weeks of 1000 mg day-1 RSV or placebo (P) followed by a 4-weeks wash-out period and subsequently 8 weeks of the opposite treatment. Primary outcome measures were heart rate and FAO as measured via stable isotope technique during constant workload exercise. Secondary outcome measures included fat and glucose metabolism; perceived exertion; as well as subjective measures of energy expenditure, fatigue, and daily function. Eight participants completed the trial. Heart rate did not differ at the end of exercise after treatment with RSV vs placebo (P = .063). Rate of oxidation of palmitate at end of exercise was not different with 1.5 ± 0.8 (RSV) vs 1.3 ± 0.6 (P) µmol kg-1  min-1 (P = .109). Secondary outcomes did not change except for increased plasma glycerol and decreased plasma glucose levels at the end of exercise after treatment with RSV vs placebo. A daily dose of 1000 mg resveratrol does not improve exercise capacity or FAO during exercise in patients with CPTII or VLCAD deficiencies.

A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation.

OBJECTIVE: Glycogen storage diseases (GSDs) are severe human disorders resulting from abnormal glucose metabolism, and all previously described GSDs segregate as autosomal recessive or X-linked traits. In this study, we aimed to molecularly characterize the first family with a dominant GSD. METHODS: We describe a dominant GSD family with 13 affected members presenting with adult-onset muscle weakness, and we provide clinical, metabolic, histological, and ultrastructural data. We performed exome sequencing to uncover the causative gene, and functional experiments in the cell model and on recombinant proteins to investigate the pathogenic effect of the identified mutation. RESULTS: We identified a heterozygous missense mutation in PYGM segregating with the disease in the family. PYGM codes for myophosphorylase, the enzyme catalyzing the initial step of glycogen breakdown. Enzymatic tests revealed that the PYGM mutation impairs the AMP-independent myophosphorylase activity, whereas the AMP-dependent activity was preserved. Further functional investigations demonstrated an altered conformation and aggregation of mutant myophosphorylase, and the concurrent accumulation of the intermediate filament desmin in the myofibers of the patients. INTERPRETATION: Overall, this study describes the first example of a dominant glycogen storage disease in humans, and elucidates the underlying pathomechanisms by deciphering the sequence of events from the PYGM mutation to the accumulation of glycogen in the muscle fibers. ANN NEUROL 2020;88:274-282.

No effect of resveratrol in patients with mitochondrial myopathy: A cross-over randomized controlled trial.

Mitochondrial myopathies (MM) are caused by mutations that typically affect genes involved in oxidative phosphorylation. Main symptoms are exercise intolerance and fatigue. Currently, there is no specific treatment for MM. Resveratrol (RSV) is a nutritional supplement that in preclinical studies has been shown to stimulate mitochondrial function. We hypothesized that RSV could improve exercise capacity in patients with MM. The study design was randomized, double-blind, cross-over and placebo-controlled. Eleven patients with genetically verified MM were randomized to receive either 1000 mg/day RSV or placebo (P) for 8 weeks followed by a 4-week washout and then the opposite treatment. Primary outcomes were changes in heart rate (HR) during submaximal cycling exercise and peak oxygen utilization (VO2 max) during maximal exercise. Secondary outcomes included reduction in perceived exertion, changes in lactate concentrations, self-rated function (SF-36) and fatigue scores (FSS), activities of electron transport chain complexes I and IV in mononuclear cells and mitochondrial biomarkers in muscle tissue among others. There were no significant differences in primary and secondary outcomes between treatments. Mean HR changes were -0.3 ± 4.3 (RSV) vs 1.8 ± 5.0 bpm (P), P = .241. Mean VO2 max changes were 0.7 ± 1.4 (RSV) vs -0.2 ± 2.3 mL/min/kg (P), P = .203. The study provides evidence that 1000 mg RSV daily is ineffective in improving exercise capacity in adults with MM. These findings indicate that previous in vitro studies suggesting a therapeutic potential for RSV in MM, do not translate into clinically meaningful effects in vivo.

Titrating a modified ketogenic diet for patients with McArdle disease: A pilot study.

Glycogen storage disease type V (GSDV) is a rare inborn error of carbohydrate metabolism. Patients present with exercise intolerance due to blocked glycogen breakdown in skeletal muscle. Introducing alternative fuel substrates, such as ketone bodies (KBs), could potentially alleviate muscle symptoms. This pilot study investigates which of three different modified ketogenic diet regimes is optimal for GSDV-patients to follow in a future large-scale study. Participants were randomised to follow one of three diet regimes for 3 weeks (#1: 65%/15%/20%; #2: 75%/15%/10%, or #3: 80%/15%/5%, fat/protein/carbohydrate). The primary outcome was exercise tolerance assessed by heart rate (HR) changes during constant load cycling. Secondary outcomes included levels of ketosis, and changes in perceived exertion and indirect calorimetry measures during exercise. Ten GSDV-patients were included. Eight completed the study. The other two were excluded. Diet #3 showed the highest average KB level (1.1 mmol/L) vs #2 (0.5 mmol/L) and #1 (0.3 mmol/L). Five patients reported subjective symptom relief, all of whom were on diets #2 and #3. All diet regimes seemed to improve fatty acid oxidation rates and exercise capacity as indicated by a small decrease in HR and perceived exertion. The results of this open-label pilot study show that diets #2 and #3 induce ketosis and improve symptoms and exercise capacity in GSDV-patients. Diet #2 had the highest acceptability score and was superior or equal to diet #3 in all other parameters, except level of ketosis. Based on this, we suggest testing diet #2 in a large-scale, placebo-controlled study in GSDV.

Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo-controlled crossover study.

In healthy individuals, postexercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance before, during, and after exercise and 2) the effect of postexercise protein-carbohydrate supplementation on muscle protein balance in patients with muscular dystrophies. In 17 patients [7 women and 10 men, aged 33 ± 11 yr (18-52), body mass index: 22 ± 3 kg/m(2) (16-26)] and 8 healthy matched controls [3 women and 5 men, age 33 ± 13 years (19-54), body mass index: 23 ± 3 kg/m(2) (19-27)], muscle protein synthesis, breakdown, and fractional synthesis rates (FSR) were measured across the leg using tracer dilution methodology on two occasions, with and without oral postexercise protein-carbohydrate supplementation. In patients, muscle protein breakdown increased in the recovery period (11 ± 1 µmol phenylalanine/min) vs. rest (8 ± 1 µmol phenylalanine/min, P = 0.02), enhancing net muscle protein loss. In contrast, postexercise protein-carbohydrate supplementation reduced protein breakdown, abolished net muscle protein loss, and increased the muscle FSR in patients (0.04 to 0.06%/h; P = 0.03). In conclusion, postexercise protein-carbohydrate supplementation reduces skeletal mixed-muscle protein breakdown, enhances FSR, resulting in a reduced net muscle loss in patients with muscular dystrophies. The findings suggest that postexercise protein-carbohydrate supplementation could be an important add-on to exercise training therapy in muscular dystrophies, and long-term studies of postexercise protein-carbohydrate supplementation are warranted in these conditions.

Aerobic fitness after JDM--a long-term follow-up study.

OBJECTIVES: It has previously been shown that patients with active JDM have decreased aerobic fitness; however, it is not known whether these patients regain their physical fitness after recovery. The objective of this study was to investigate the long-term outcome of aerobic fitness in patients with JDM. We hypothesized that fitness (VO(2max)) is reduced compared with healthy controls in the years after active JDM. METHODS: A maximal exercise test was performed using a cycle ergometer. Results were compared with those of sex- and age-matched healthy controls. RESULTS: A total of 36 patients with JDM in remission were included, 2-36 years after disease onset. Twelve patients (33%) had normal VO(2max) and 24 patients (67%) had decreased VO(2max). Mean VO(2max) was higher in the healthy controls vs patients (P < 0.001, 95% CI -10.7, -4.4). A significant difference between patients with JDM and controls was observed for women (P < 0.001), men (P = 0.04), children < 18 years (P = 0.002) and adults > 18 years (P = 0.01). The decreased VO(2max) was independent of the duration of remission, but it was associated with the duration of active disease. By linear regression, it was revealed that for every year of active disease, VO(2max) was reduced by 0.85 ml/min/kg on average (P < 0.001). CONCLUSION: This long-term follow-up study demonstrates that patients who have had JDM have persistently impaired fitness. This impairment is directly related to the duration of active disease.

Muscle phenotype in patients with myotonic dystrophy type 1.

INTRODUCTION: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. METHODS: In 38 patients, muscle strength was tested by hand-held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na(+)-K(+) pump content. RESULTS: Muscle strength correlated with a decline in Na(+)-K(+) pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na(+)-K(+) pump content. Histopathologically, we found few centrally placed nuclei (range 0.2-6.9%). CONCLUSIONS: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1.

Impaired lipolysis in propionic acidemia: A new metabolic myopathy?

The objective of this study was to investigate the fat and carbohydrate metabolism in a patient with propionic acidemia (PA) during exercise by means of indirect calorimetry and stable isotope technique. A 34-year-old patient with PA performed a 30-minute submaximal cycle ergometer test. Data were compared to results from six gender- and age-matched healthy controls. Main findings are that the patient with PA had impaired lipolysis, blunted fatty acid oxidation, compensatory increase in carbohydrate utilization, and low work capacity. Our findings indicate that PA should be added to the list of metabolic myopathies.

Effect of Aerobic Exercise Training and Deconditioning on Oxidative Capacity and Muscle Mitochondrial Enzyme Machinery in Young and Elderly Individuals.

Mitochondrial dysfunction is thought to be involved in age-related loss of muscle mass and function (sarcopenia). Since the degree of physical activity is vital for skeletal muscle mitochondrial function and content, the aim of this study was to investigate the effect of 6 weeks of aerobic exercise training and 8 weeks of deconditioning on functional parameters of aerobic capacity and markers of muscle mitochondrial function in elderly compared to young individuals. In 11 healthy, elderly (80 ± 4 years old) and 10 healthy, young (24 ± 3 years old) volunteers, aerobic training improved maximal oxygen consumption rate by 13%, maximal workload by 34%, endurance capacity by 2.4-fold and exercise economy by 12% in the elderly to the same extent as in young individuals. This evidence was accompanied by a similar training-induced increase in muscle citrate synthase (CS) (31%) and mitochondrial complex I-IV activities (51-163%) in elderly and young individuals. After 8 weeks of deconditioning, endurance capacity (-20%), and enzyme activity of CS (-18%) and complex I (-40%), III (-25%), and IV (-26%) decreased in the elderly to a larger extent than in young individuals. In conclusion, we found that elderly have a physiological normal ability to improve aerobic capacity and mitochondrial function with aerobic training compared to young individuals, but had a faster decline in endurance performance and muscle mitochondrial enzyme activity after deconditioning, suggesting an age-related issue in maintaining oxidative metabolism.

Exercise tolerance in carnitine palmitoyltransferase II deficiency with IV and oral glucose.

BACKGROUND: Patients with carnitine palmitoyltransferase II (CPT II) deficiency often experience muscle pain and myoglobinuria during prolonged exercise because of impaired oxidation of long-chain fatty acids. OBJECTIVE: To investigate whether IV or oral glucose can improve exercise tolerance in CPT II deficiency. METHODS: Five patients with CPT II deficiency and healthy matched volunteers were investigated on a cycle ergometer at a constant workload of 60% of VO(2max). Perceived exertion, heart rate, and venous plasma glucose and insulin levels were monitored. The study was randomized, placebo controlled, single blind, and crossover. Glucose and placebo were administered both orally and IV in patients and IV in healthy subjects. RESULTS: In patients with CPT II, exercise duration was prolonged by 28 +/- 8% (p = 0.02), and perceived exertion (p = 0.05) and heart rate (p = 0.09) were lowered by glucose infusion. In contrast, IV glucose resulted in higher heart rate during exercise in healthy subjects. Oral glucose and placebo resulted in the same exercise duration, perceived exertion, and heart rate in patients. Plasma glucose and insulin were consistently elevated during exercise by oral and IV glucose vs placebo, but plasma glucose was higher and insulin lower in IV vs oral glucose studies in patients (p = 0.02). CONCLUSION: Exercise tolerance is markedly improved by a glucose infusion in patients with CPT II deficiency, but because of lower glucose availability and higher insulin levels that inhibit muscle glycogenolysis, the patients cannot achieve this effect themselves by oral glucose ingestion.

Muscle structural changes in mitochondrial myopathy relate to genotype.

It is well known that morphological changes at the cellular level occur in muscle of patients with mitochondrial myopathy (MM), but changes in muscle structure with fat infiltration and gross variation of muscle fiber size with giant fibers, normally encountered in the muscular dystrophies, have typically not been associated with mitochondrial disease. We investigated gross and microscopic muscle morphology in thigh muscles by muscle biopsy and MRI in 16 patients with MM, and compared findings with those obtained in muscular dystrophy patients and healthy subjects. Changes of muscle architecture, similar to those found in the group of muscular dystrophy patients occurred consistently in patients with a high mutation load for single, largescale deletions of mtDNA, but were absent in all patients with the 3243A-->G mtDNA point mutation. Dystrophic changes of muscle architecture were also present in one MM patient with a unique, sporadic mutation in the mtDNA tRNA(Met) gene. These findings provide evidence that morphological changes in muscle of MM patients are common and may resemble those of muscular dystrophies, but that development of dystrophic-like changes in muscle relate to genotype.

Lactate metabolism during exercise in patients with mitochondrial myopathy.

Patients with mitochondrial DNA mutations often have elevated plasma lactate at rest and during exercise, but it is unknown whether the high lactate levels are caused by a high production, an impaired oxidation or a combination. We studied lactate kinetics in 10 patients with mtDNA mutations and 10 matched healthy control subjects at rest and during cycle exercise with a combination of femoral arterio-venous differences of lactate, and lactate tracer dilution methodology. During exercise, lactate concentration and production rates were several-fold higher in patients, but despite mitochondrial dysfunction, lactate was oxidized in muscle to the same extent as in healthy control subjects. This surprisingly high ability to burn lactate in working muscle with defective mitochondria, probably relates to the variability of oxidative capacity among muscle fibers. The data suggests that lactate is not solely an indicator of impaired oxidative capacity, but an important fuel for oxidative metabolism, even in muscle with severely impaired mitochondrial function.

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.

Aerobic training in patients with myotonic dystrophy type 1.

The effect of 12 weeks of aerobic training on a cycle ergometer was studied in 12 patients with myotonic dystrophy. Efficacy was evaluated by cycle testing and muscle morphology before and after training. Patients increased their maximal oxygen uptake by 14%, the maximal workload by 11%, muscle fiber diameter increased significantly, and creatine kinase did not increase with training. The study indicates that aerobic training is safe and can improve fitness effectively in patients with myotonic dystrophy.

Fuel utilization in subjects with carnitine palmitoyltransferase 2 gene mutations.

Patients with the myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency typically experience muscle pain, cramps, and myoglobinuria during prolonged exercise. It has been suggested that carriers of CPT2 gene mutations also may have milder clinical symptoms, but fatty acid oxidation (FAO) has never been investigated in vivo in this group. We studied fuel utilization by indirect calorimetry and stable isotope methodology in four patients with CPT II deficiency, three subjects who carried one CPT2 gene mutation, and five healthy control subjects. Cycle exercise at a constant workload of 50% of maximal oxygen uptake capacity was used to facilitate FAO. We found that in vivo oxidation of long-chain fatty acids was normal at rest but severely impaired during prolonged, low-intensity exercise in patients with CPT II deficiency, and that two of the single CPT2 gene mutation carriers, who displayed symptoms of CPT II deficiency, had an FAO comparable with the patients. These results indicate that residual CPT II activity is sufficient to maintain long-chain FAO at rest in CPT II deficiency but not to increase FAO during exercise. The findings also suggest that single CPT2 gene mutations may exert a dominant-negative effect on the tetrameric CPT II protein.

Effect of diet on exercise tolerance in carnitine palmitoyltransferase II deficiency.

It is generally believed that a diet high in carbohydrate improves exercise tolerance in patients with carnitine palmitoyltransferase II (CPT II) deficiency, but it has never been systematically investigated. The authors investigated the effect of a high- vs low-carbohydrate diet on exercise tolerance in four patients with CPT II, who cycled at a constant workload of 50% of VO2max. Exercise tolerance, assessed by exercise duration and perceived exertion, improved on the carbohydrate-rich diet.

Fuel utilization in patients with very long-chain acyl-coa dehydrogenase deficiency.

Fuel utilization in two adult patients with the myopathic form of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and five healthy subjects was investigated with stable isotopes during exercise at 50% of VO2max. The findings indicate that residual VLCAD activity in the patients is sufficient to maintain normal oxidation of fat at rest, but that fat oxidation rate cannot increase above basal levels during exercise. This can cause an energy deficit and intramuscular accumulation of fat intermediates that may induce the exercise-induced symptoms.