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.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective degeneration of motor neurons in the brain and spinal cord that leads to muscle weakness, paralysis and death usually due to respiratory failure [1]
Given the effect of triheptanoin on motor function in hSOD1G93A mice, we aimed to evaluate the extent to which tricarboxylic acid (TCA) cycle metabolism or anaplerosis may be impaired in the gastrocnemius muscle of hSOD1G93A mice in the early and late stages of the disease
The most important findings of this study are that 1) triheptanoin attenuated motor neuron loss in hSOD1G93A mice, 2) triheptanoin delayed the onset of motor symptoms in hSOD1G93A mice, and 3) decreased expression of muscle enzyme mRNA involved in TCA cycling in hSOD1G93A mice was attenuated by triheptanoin
Summary
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective degeneration of motor neurons in the brain and spinal cord that leads to muscle weakness, paralysis and death usually due to respiratory failure [1]. Ninety percent of ALS cases are sporadic (SALS), while 10% are familial (FALS) [3]. Mutations in genes such as superoxide dismutase 1 (SOD1) [4], TAR DNA-Binding Protein (TDP 43) [5], fused in sarcoma (FUS) [6], Ubiquilin (UBQLN2) [7], and C9ORF72 [8,9] are implicated in genetic causes of ALS. Twenty percent of familial ALS cases are linked to mutations in the SOD1 gene (most commonly occurring mutation in patients with FALS) and this accounts for 1 to 2% of all forms of ALS while FUS and TDP-43 mutations account for 5% of FALS cases [3,10]. While the normal SOD1 protein is usually found in the cytosol, mutant SOD1 accumulates within mitochondria and appears to contribute to many of the mitochondrial perturbations observed in ALS [11,12,13,14,15]
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