Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice

BACKGROUND: Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD. METHODS AND FINDINGS: Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice. CONCLUSIONS: These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Peer reviewe

Resting oxygen consumption and in vivo ADP are increased in myopathy due to complex I deficiency

Background: Patients with isolated complex I deficiency (CID) in skeletal muscle mitochondria often present with exercise intolerance as their major clinical symptom. Objective: To study the in vivo bioenergetics in patients with complex I deficiency in skeletal muscle mitochondria. Methods: In vivo bioenergetics were studied in three of these patients by measuring oxygen uptake at rest and during maximal exercise, together with forearm ADP concentrations ([ADP]) at rest. Whole-body oxygen consumption at rest (Vo(2)) was measured with respiratory calorimetry. Maximal oxygen uptake (Vo(2)max) was measured during maximal exercise on a cycle ergometer. Resting [ADP] was estimated from in vivo P-31 MRS measurements of inorganic phosphate, phosphocreatine, and ATP content of forearm muscle. Results: Resting Vo(2) was significantly increased in all three patients: 128 +/- 14% (SD) of values in healthy control subjects. Vo(2)max in patients was on average 2.8 times their Vo(2) at rest and was only 28% of Vo(2)max in control subjects. Resting [ADP] in forearm muscle was significantly increased compared with healthy control subjects (patients 26 +/- 2 muM, healthy controls 9 +/- 2 muM). Conclusion: In patients with CID, the increased whole-body oxygen consumption rate at rest reflects increased electron transport through the respiratory chain, driven by a decreased phosphorylation potential, The increased electron transport rate may compensate for the decreased efficiency of oxidative phosphorylation (phosphorylation potential)

Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise

We studied the role of lactate in gluconeogenesis (GNG) during exercise in untrained fasting humans. During the final hour of a 4-h cycle exercise at 33-34% maximal O-2 uptake, seven subjects received, in random order, either a sodium lactate infusion (60 mumol.kg(-1).min(-1)) or an isomolar sodium bicarbonate infusion. The contribution of lactate to gluconeogenic glucose was quantified by measuring H-2 incorporation into glucose after body water was labeled with deuterium oxide, and glucose rate of appearance (R-a) was measured by[6,6-H-2(2)] glucose dilution. Infusion of lactate increased lactate concentration to 4.4 +/- 0.6 mM (mean +/- SE). Exercise induced a decrease in blood glucose concentration from 5.0 +/- 0.2 to 4.2 +/- 0.3 mM (P <0.05); lactate infusion abolished this decrease (5.0 &PLUSMN; 0.3 mM; P <0.001) and increased glucose R-a compared with bicarbonate infusion (P <0.05). Lactate infusion increased both GNG from lactate (29 &PLUSMN; 4 to 46 &PLUSMN; 4% of glucose R-a, P L 0.001) and total GNG. We conclude that lactate infusion during low-intensity exercise in fasting humans 1) increased GNG from lactate and 2) increased glucose production, thus increasing the blood glucose concentration. These results indicate that GNG capacity is available in humans after an overnight fast and can be used to sustain blood glucose levels during low-intensity exercise when lactate, a known precursor of GNG, is available at elevated plasma levels