Palamiuc L.,French Institute of Health and Medical Research |
Palamiuc L.,University of Strasbourg |
Schlagowski A.,University of Strasbourg |
Schlagowski A.,Pole Of Pathologie Thoracique Hopitaux Universitaires |
And 17 more authors.
EMBO Molecular Medicine | Year: 2015
Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease (SOD1G86R), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1G86R mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
Lejay A.,Institute Of Physiologie |
Lejay A.,Hopitaux Universitaires |
Meyer A.,Institute Of Physiologie |
Meyer A.,Pole Of Pathologie Thoracique Hopitaux Universitaires |
And 13 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2014
Irrespective of the organ involved, restoration of blood flow to ischemic tissue is vital, although reperfusion per se is deleterious. In the setting of vascular surgery, even subtle skeletal muscle ischemia contributes to remote organ injuries and perioperative and long-term morbidities. Reperfusion-induced injury is thought to participate in up to 40% of muscle damage. Recently, the pathophysiology of lower limb ischemia-reperfusion (IR) has been largely improved, acknowledging a key role for mitochondrial dysfunction mainly characterized by impaired mitochondrial oxidative capacity and premature mitochondrial permeability transition pore opening. Increased oxidative stress triggered by an imbalance between reactive oxygen species (ROS) production and clearance, and facilitated by enhanced inflammation, appears to be both followed and instigated by mitochondrial dysfunction. Mitochondria are both actors and target of IR and therapeutic strategies modulating degree of ROS production could enhance protective signals and allow for mitochondrial protection through a mitohormesis mechanism. © 2014 Published by Elsevier Ltd.
Wolff V.,University of Strasbourg |
Wolff V.,Hopitaux Universitaires Of Strasbourg |
Wolff V.,CNRS Computer Science and Engineering Laboratory |
Schlagowski A.-I.,University of Strasbourg |
And 14 more authors.
BioMed Research International | Year: 2015
Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities V max (complexes I, III, and IV activities), V succ (complexes II, III, and IV activities), V tmpd (complex IV activity), together with mitochondrial coupling (V max / V 0), were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H production, measured with Amplex Red. THC significantly decreased V max (-71%; P < 0.0001), V succ (-65%; P < 0.0001), and V tmpd (-3.5%; P < 0.001). Mitochondrial coupling (V max / V 0) was also significantly decreased after THC exposure (1.8 ± 0.2 versus 6.3 ± 0.7; P < 0.001). Furthermore, THC significantly enhanced Hproduction by cerebral mitochondria (+171%; P < 0.05) and mitochondrial free radical leak was increased from 0.01 ± 0.01 to 0.10 ± 0.01 % (P < 0.001). Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patient's vulnerability to stroke. © 2015 Valérie Wolff et al.