New research has identified mitochondrial therapies that may benefit people who suffer from certain types of inherited neuromuscular disorders. Neuromuscular disorders affect a large number of children and adults worldwide, and mitochondrial involvement characterizes roughly 1 in 5,000 cases. Currently, treatments for mitochondrial diseases may relieve symptoms but do not target the disease itself.

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Carlos T. Moraes and colleagues at the University of Miami School of Medicine (Miami, FL) and Dana-Farber Cancer Institute (Boston, MA) attempted to address mitochondrial myopathy by increasing mitochondrial functional mass. They used mice in which the gene encoding an essential cytochrome oxidase assembly factor was deactivated, resulting in a progressive myopathy with a pattern similar to that observed in human mitochondrial myopathies. The team worked with two different varieties of the knockout mice: a 'severe myopathy' model and a 'mild myopathy' model.

The team studied two different approaches to mitochondrial therapy. Both treatments work by boosting the activity of peroxisome proliferator-activated receptor γ (PPARγ) coactivator α (PGC-1α). PGC-1α is a metabolic regulator and is known to have a role in controlling mitochondrial biogenesis.

First, Moraes et al. analyzed the effects of induced mitochondrial biogenesis on disease course by crossing both varieties of knockout mice with a third mouse line engineered to express PGC-1α in muscle. Knockout mice expressing PGC-1α survived markedly longer than control knockout mice that did not express the transgene, particularly among female mice (Cell Metab. 8, 249–256; 2008). In addition, muscle impairment took longer to develop in knockout mice expressing PGC-1α than in those without PGC-1α.

In a second approach, Moraes's group investigated whether administering bezafibrate to knockout mice could increase mitochondrial biogenesis. Bezafibrate is a drug that stimulates the PGC-1α/PPAR pathway. Knockout mice that received bezafibrate lived significantly longer than littermates that did not receive the drug. In addition, disease onset was delayed in bezafibrate-fed mice compared with knockouts fed a normal diet.

The researchers concluded that increased mitochondrial proliferation in muscle was able to delay the onset of mitochondrial myopathy in the knockout mice, resulting in a longer lifespan. These benefits were likely due to increased mitochondrial mass in muscle tissue. The authors believe that their therapeutic strategies may also be applicable to other mitochondrial diseases. “The promising results with the bezafibrate-fed myopathy mice clearly identify small-molecule PPAR agonists, already used in humans with metabolic diseases, as a treatment option for mitochondrial diseases,” concluded their report.