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.

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.

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.