Karen Lindhardt Madsen

Mutations in mitochondrial DNA (mtDNA) cause disruption of the oxidative phosphorylation chain and impair energy production in cells throughout the human body. Primary mitochondrial disorders due to mtDNA mutations can present with symptoms from adult-onset mono-organ affection to death in infancy due to multi-organ involvement. The heterogeneous phenotypes that patients with a mutation of mtDNA can present with are thought, at least to some extent, to be a result of differences in mtDNA mutation load among patients and even among tissues in the individual. The most common symptom in patients with mitochondrial myopathy (MM) is exercise intolerance. Since mitochondrial function can be assessed directly in skeletal muscle, exercise studies can be used to elucidate the physiological consequences of defective mitochondria due to mtDNA mutations. Moreover, exercise tests have been developed for diagnostic purposes for mitochondrial myopathy. In this review, we present the rationale for exercise testing of patients with MM due to mutations in mtDNA, evaluate the diagnostic yield of exercise tests for MM and touch upon how exercise tests can be used as tools for follow-up to assess disease course or effects of treatment interventions.

Objective To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy. Methods In cohorts of 8–13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory). Results No differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent. Conclusions Omaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group. Clinicaltrials.gov identifier NCT02255422. Classification of evidence This study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.

Objective To investigate substrate metabolism during exercise in an adult with lipin-1 deficiency, an inherited defect in lipid homeostasis, and to study the effect of glucose supplementation on his exercise tolerance. Methods We studied a 48-year-old man with lipin-1 deficiency and 2 healthy men. The patient has exercise intolerance and monthly episodes of rhabdomyolysis. All participants performed a submaximal exercise test while total fatty acid oxidation (FAO) and palmitate oxidation rate were assessed by stable isotope technique and indirect calorimetry. On another day, the patient was infused with 10% glucose (410 mL/h) and repeated the exercise. On the third and fourth visits, he was randomized in a double-blind manner to drink a supplement of glucose (soft drink 2% concentration) or placebo (soft drink: aspartame, acesulfame-K) before and during exercise. Results Mean FAO and palmitate oxidation rate during exercise were lower in the patient vs controls: 431 vs 1,271 and 1912 μmol/min and 122 vs 191 and 212 μmol/min. Plasma fatty acid concentration was lower in the patient during exercise than in controls: 477 vs 643 and 630 μmol/L. The patient9s exercise duration increased from 36 to 60 minutes with IV glucose and 46 minutes with oral glucose, and his rating of exertion dropped from 15 to 9 on average (Borg scale). Conclusion In this adult lipin-1–deficient patient, FAO was reduced, which was associated with no increase in plasma free fatty acids during submaximal exercise, and his exercise capacity improved with continuous ingestion of high-dose glucose. ClinicalTrials.gov identifier NCT02635269.

Objective: To study if treatment with triheptanoin, a 7‐carbon triglyceride, improves exercise tolerance in patients with McArdle disease. McArdle patients have a complete block in glycogenolysis and glycogen‐dependent expansion of tricarboxylic acid cycle (TCA), which may restrict fat oxidation. We hypothesized that triheptanoin metabolism generates substrates for the TCA, which potentially boosts fat oxidation and improves exercise tolerance in McArdle disease.Methods: Double‐blind, placebo‐controlled, crossover study in patients with McArdle disease completing two treatment periods of 14 days each with a triheptanoin or placebo diet (1 g/kg/day). Primary outcome was change in mean heart rate during 20 min submaximal exercise on a cycle ergometer. Secondary outcomes were change in peak workload and oxygen uptake along with changes in blood metabolites and respiratory quotients.Results: Nineteen of 22 patients completed the trial. Malate levels rose on triheptanoin treatment versus placebo (8.0 ± SD2.3 vs. 5.5 ± SD1.8 µmol/L, P < 0.001), but dropped from rest to exercise (P < 0.001). There was no difference in exercise heart rates between triheptanoin (120 ± SD16 bpm) and placebo (121 ± SD16 bpm) treatments. Compared with placebo, triheptanoin did not change the submaximal respiratory quotient (0.82 ± SD0.05 vs. 0.84 ± SD0.03), peak workload (105 ± SD38 vs. 102 ± SD31 Watts), or peak oxygen uptake (1938 ± SD499 vs. 1977 ± SD380 mL/min).Interpretation: Despite increased resting plasma malate with triheptanoin, the increase was insufficient to generate a normal TCA turnover during exercise and the treatment has no effect on exercise capacity or oxidative metabolism in patients with McArdle disease.

Context: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) affects oxidation of long-chain fatty acids (FAO) and is associated with risk of metabolic crises and episodic rhabdomyolysis.Case Description: We present the cases of two patients with LCHADD. Patient 1 (male, 26 years old) was severely affected by muscle weakness and neuropathy. He was diagnosed at age 20 years and was nonadherent to standard dietary management. MRI revealed significant fat replacement of muscle in both calves. Patient 2 (female, 15 years old) was diagnosed at age 1 year. She had no muscle weakness and was compliant with the recommended diet. Compared with healthy persons, both patients had reduced FAO and palmitate oxidation, measured with indirect calorimetry and stable isotope technique during a submaximal cycle ergometer test. Patient 2 had some residual capacity to increase FAO and a compensatory higher carbohydrate oxidation, which ensured a near-normal exercise capacity. Patient 1 was unable to increase FAO and could only complete 23 minutes of exercise, vs 60 minutes by patient 2 and healthy persons. In both, 10% IV infusion of glucose (IV-glucose) during exercise increased carbohydrate oxidation slightly, but endurance was not improved, which likely relates to the fixed weakness in patient 1 and because the residual FAO was suppressed by the glucose infusion in both.Conclusion: The two patients illustrate that FAO is impaired and carbohydrate oxidation is elevated during exercise in patients affected by LCHADD, compared with healthy persons, but IV-glucose has no beneficial effect on exercise tolerance in LCHADD.

We investigated the in vivo skeletal muscle metabolism in patients with multiple acyl‐CoA dehydrogenase deficiency (MADD) during exercise, and the effect of a glucose infusion. Two adults with MADD on riboflavin and l‐carnitine treatment and 10 healthy controls performed an incremental exercise test measuring maximal oxidative capacity (VO_2max) and a submaximal exercise test (≤1 hour) on a cycle ergometer. During submaximal exercise, we studied fat and carbohydrate oxidation, using stable isotope tracer methodology and indirect calorimetry. On another day, the patients repeated the submaximal exercise receiving a 10% glucose infusion. The patients had a lower VO_2max than controls and stopped the submaximal exercise test at 51 and 58 minutes due to muscle pain and exhaustion. The exercise‐induced increase in total fatty acid oxidation was blunted in the patients (7.1 and 1.1 vs 12 ± 4 μmol × kg⁻¹ × min⁻¹ in the healthy controls), but total carbohydrate oxidation was higher (67 and 63 vs 25 ± 11 μmol × kg⁻¹ × min⁻¹ in controls). With glucose infusion, muscle pain decreased and average heart rate during exercise dropped in both patients from 124 to 119 bpm and 138 to 119 bpm. We demonstrate that exercise intolerance in MADD‐patients relates to an inability to increase fat oxidation appropriately during exercise, which is compensated partially by an increase in carbohydrate metabolism.

Context Primary Carnitine Deficiency (PCD) is an inborn error of fatty acid metabolism. PCD patients risk 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 Subjects Eight adults with PCD, homozygous for the c.95A>G (p.N32S) mutation, and ten healthy age- and sex-matched controls. Intervention Pause in L-carnitine treatment for four days. Main outcome measures Total fatty acid and palmitate oxidation rates during 1-hour submaximal cycle ergometer exercise assessed with stable isotope methodology (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, in L-carnitine treated patients, the fatty acid oxidation rate was still less than in the healthy controls (29.5 SD 10.1 µmol×kg^-1×min^-1) p-1×min^-1) vs. on treatment (204 SD 84 µmol×kg^-1×min^-1), p=0.004. Conclusions Our results indicate that PCD-patients have a limited fat oxidation during exercise. L-carnitine treatment in asymptomatic PCD-patients may not only prevent cardiac complications, but also boost skeletal muscle fat metabolism during exercise.

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.