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.

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

No effect of triheptanoin in patients with phosphofructokinase deficiency.

Phosphofructokinase deficiency (PFKD) is a rare disorder of glycogen metabolism. The lack of phosphofructokinase activity blocks the oxidative pathway from glucose and glycogen to pyruvate. Patients suffer from myopathy, exercise intolerance, and myoglobinuria. Currently, there is no specific treatment for PFKD. We hypothesized that 2 weeks treatment with triheptanoin could improve oxidative metabolism during exercise by bypassing the blocked pyruvate generation in PFKD. The study was a randomized, double-blind, placebo-controlled crossover study. Three genetically verified patients completed two treatment periods of 14 days each with triheptanoin (0.3-1 g × kg-1 × day-1) or placebo liquid. Primary outcomes were heart rate, fatty acid and total oxidation measured via stable isotope and indirect calorimetry methodology during submaximal exercise. Triheptanoin did not improve the primary outcome heart rate during submaximal exercise compared to placebo. Palmitate oxidation was increased during submaximal exercise in one patient but did not increase in the two other patients during triheptanoin treatment. Palmitate production and palmitate utilization increased during exercise and increased to a greater extent with triheptanoin treatment in all three patients. This study suggests that triheptanoin treatment has no effect on heart rate or exercise performance despite increased palmitate production and utilization in patients with PFKD.

Plasma lactate responses during and after submaximal handgrip exercise are not diagnostically helpful in mitochondrial myopathy.

INTRODUCTION/BACKGROUND: Mitochondrial myopathy (MM) encompasses a clinical heterogenous group of patients that can be difficult to diagnose. The aim of this study was to investigate if changes in plasma lactate concentration during a 6-minute submaximal handgrip test (6MHGT) and a 20-minute post-exercise recovery period can be used as a diagnostic test for MM. METHODS: Twenty-nine patients with MM and nineteen healthy controls (HC) performed an intermittent handgrip exercise test at ½ Hz for 6 min at 50% of maximal voluntary contraction force. We calculated the area under the curve (AUC) of change in plasma lactate during exercise and recovery and compared AUC between groups (MM vs. HC, and between MM subgroups based on disease severity). RESULTS: The change in plasma lactate during exercise and recovery was similar in MM and HC (p = 0.65 and p = 0.57) and similar between MM subgroups (p ≥ 0.24). CONCLUSION: Plasma lactate measured during and after a submaximal 6MHGT cannot be used as a diagnostic variable for MM.