Pilot study of the treatment of patients with sporadic Inclusion Body Myositis with the Anaplerotic medication Triheptanoin

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Sporadic Inclusion body myositis is the most common acquired muscle disorder in patients over the age of 50. The cause of IBM is not known and there is no effective therapy. IBM is a slowly progressive disorder with increasing weakness and muscle atrophy involving particularly the thighs, long finger flexors and bulbar muscles resulting in progressive loss of mobility, loss of hand function and impaired swallowing. It progresses to disability over 5-10 years with wheel chair dependence, loss of hand function, impaired nutrition due to inability to swallow, increasing debility and susceptibility to aspiration. Theories for IBM pathogensesis can be divided into primary inflammatory hypotheses and primary degenerative hypotheses. Treating IBM with immunosuppression is not effective and steroids may accelerate the disorder possibly by stimulating catabolic pathways. Degenerative hypotheses can be grouped into several catagories, myofiber injury by beta-amyloid, myofiber injury due to other accumulated molecules, a myonuclear disorder, a disorder of protein degradation and a disorder of mitochondria. The most consistent finding in IBM is an abnormality of protein degradation with accumulation of degradation products in autophagic vacuoles. There is also a deficit in Proteosome 26-ubiquitin protein degradation. The proteosome-ubiquitin and autophagy pathways are activated in the presence of energy depletion and starvation to provide an alternate source of energy to fuel the citric acid cycle and maintain energy homeostasis. It is not certain as to whether there is an acceleration of protein breakdown or a defect of disposal of breakdown products or both in IBM. The crucial protein and organelle disposal pathway of autophagy is critically overloaded and this is probably the most important mechanism for myofibre damage. It is probable that this overloading is the result of catabolic pathway acceleration and this may result from a deficit in energy metabolism leading to activation of the catabolic cascade. Progressive muscle atrophy and increasing weakness indicate the predominance of protein catabolic over anabolic activities in IBM. It is hypothesised that repairing energy deficits and increasing anabolic activity will be beneficial in IBM and will in turn inhibit and “switch off” the harmful autophagic process. Trihepatanoin (TGC7) is a triglyceride containing three C7 fatty acid chains. After cleavage in the gut, heptanoate is absorbed through the gut and can be metabolised in most tissues. As a medium chain fatty acid, uptake into mitochondria is via diffusion and independent from the shuttle system, thereby providing fast energy. Each heptanoate provides both substrate (acyl CoA) and intermediates (oxaloacetate; via carboxylation of propionyl-CoA) for the CAC in muscle and brain. Therefore, TGC7 has the ability to refuel the CAC, increase ATP production and reverse the catabolic cascade. It is hypothesised that administering Triheptanoin, up to 30% of daily caloric requirement, by fuelling the CAC to enhance anabolic pathways and inhibit catabolism will have a significant benefit in the treatment of IBM to maintain and improve muscle strength and swallowing.

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