title: Triheptanoin Protects Motor Neurons and Delays the Onset of Motor Symptoms in a Mouse Model of Amyotrophic Lateral Sclerosis.
abstract: There is increasing evidence that energy metabolism is disturbed in Amyotrophic Lateral Sclerosis (ALS) patients and animal models. Treatment with triheptanoin, the triglyceride of heptanoate, is a promising approach to provide alternative fuel to improve oxidative phosphorylation and aid ATP generation. Heptanoate can be metabolized to propionyl-CoA, which after carboxylation can produce succinyl-CoA and thereby re-fill the tricarboxylic acid (TCA) cycle (anaplerosis). Here we tested the hypothesis that treatment with triheptanoin prevents motor neuron loss and delays the onset of disease symptoms in female mice overexpressing the mutant human SOD1G93A (hSOD1G93A) gene. When oral triheptanoin (35% of caloric content) was initiated at P35, motor neuron loss at 70 days of age was attenuated by 33%. In untreated hSOD1G93A mice, the loss of hind limb grip strength began at 16.7 weeks. Triheptanoin maintained hind limb grip strength for 2.8 weeks longer (p<0.01). Loss of balance on the rotarod and reduction of body weight were delayed by 13 and 11 days respectively (both p<0.01). Improved motor function occurred in parallel with alterations in the expression of genes associated with muscle metabolism. In gastrocnemius muscles, the mRNA levels of pyruvate, 2-oxoglutarate and succinate dehydrogenases and methyl-malonyl mutase were reduced by 24-33% in 10 week old hSOD1G93A mice when compared to wild-type mice, suggesting that TCA cycling in skeletal muscle may be slowed in this ALS mouse model at a stage when muscle strength is still normal. At 25 weeks of age, mRNA levels of succinate dehydrogenases, glutamic pyruvic transaminase 2 and the propionyl carboxylase β subunit were reduced by 69-84% in control, but not in triheptanoin treated hSOD1G93A animals. Taken together, our results suggest that triheptanoin slows motor neuron loss and the onset of motor symptoms in ALS mice by improving TCA cycling.
authors: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors: Tesfaye W
authors: TW
authors: Tefera
authors: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors: Yide
authors: Y
authors: Wong
authors: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors: Mallory E
authors: ME
authors: Barkl-Luke
authors: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.|University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia.
authors: Shyuan T
authors: ST
authors: Ngo
authors: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors: Nicola K
authors: NK
authors: Thomas
authors: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors: Tanya S
authors: TS
authors: McDonald
authors: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors: Karin
authors: K
authors: Borges
mesh_terms: D000410:Alanine Transaminase / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects; D005260:Female; D018737:Hand Strength / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000187:drug effects*; D013385:Succinate Dehydrogenase / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D014280:Triglycerides / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D014280:Triglycerides; C531010:triheptanoin; D000072105:Superoxide Dismutase-1; D013385:Succinate Dehydrogenase; D000410:Alanine Transaminase