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.

Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

“…However, there are indications of defects in the glucose metabolizing pathways in ALS namely in the glycolysis and the TCA cycle pathways in CNS and muscle (Palamiuc et al, 2015; Tefera et al, 2016). In addition, there is decreased glucose uptake in numerous brain regions and spinal cord of animal models and patients with ALS (Dalakas et al, 1987; Hatazawa et al, 1988; Ludolph et al, 1992; Browne et al, 2006; Miyazaki et al, 2012; Cistaro et al, 2014).…”

“…In muscle, namely the tibialis anterior muscle of the superoxide dismutase 1 (SOD1 G86R ) mice, the activities of the enzyme phosphofructokinase 1 (PFK1), the rate limiting enzyme in glycolysis, were reduced (Palamiuc et al, 2015). Furthermore, in the gastrocnemius muscle of SOD1 G93A mice, the activities of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH) were found to be reduced in the late symptomatic phases of the disease, indicating impairments in the TCA cycle pathway (Tefera et al, 2016). Furthermore, changes in the expression of several genes involved in energy metabolism have been observed in muscle, brain and spinal cord tissues and cells isolated from them.…”

“…A number of studies have tried to correct the energy deficit using metabolic therapies in animal models and patients with ALS, with the hope that an improved metabolism can delay symptoms and extend survival in ALS (Dupuis et al, 2004; Zhao et al, 2006, 2012; Mattson et al, 2007; Miquel et al, 2012; Ari et al, 2014; Wills et al, 2014; Palamiuc et al, 2015; Tefera et al, 2016). A study by Dupuis et al (2004) in SOD1 G86R mice found aberrations of energy metabolism such as reduction of adiposity, increased energy expenditure and lipolysis, and examined the effects of a high fat diet that consisted of regular chow supplemented with 21% (wt/wt) butter fat and 0.15% (wt/wt) cholesterol.…”

“…Cognisant of the positive effects of triheptanoin in other brain and neuromuscular disorders and its mechanism of action, we hypothesized that treatment with triheptanoin, being an alternative substrate to glucose provides degenerating cells with much needed energy, which can delay cell death and thereby the onset of motor symptoms in the ALS mouse model. Thus we recently investigated the effects of triheptanoin in the hSOD1 G93A mice (Tefera et al, 2016). …”

Energy metabolism in amyotrophic lateral sclerosis: assessment of body composition and energy expenditure

“…Other dietary modifications that aim to alter energy substrate supply and/or promote anaplerosis (replenishing depleted metabolic intermediates), including the ketogenic diet , the "Deanna protocol" (Fournier et al, 2013, Ari et al, 2014 and triheptanoin (Tefera et al, 2016), could potentially be useful in treating the energy deficit in ALS, but need further formal testing.…”