NEUROTROPHIN-4 IS UP-REGULATED IN RAGGED-RED FIBERS ASSOCIATED WITH PATHOGENIC MITOCHONDRIAL-DNA MUTATIONS

Ragged-red fibers (RRFs) are found more frequently in highly oxidative type I fibers than in glycolytic type II fibers in the muscle of many patients with mitochondrial myopathies. Neurotrophin-4 (NT-4), a neur onal signaling molecule, is also expressed in skeletal muscle, predomi nantly in type I fibers. We found that NT-4 protein and mRNA were pres ent in both type I and type II fibers but were up-regulated in RRFs of patients with mitochondrial encephalomyopathies; it is noteworthy tha t NT-4 was not up-regulated in muscle fibers from healthy aerobically trained athletes. Thus, NT-4 might represent a member of a new class o f candidate molecules involved in the compensatory adjustments of musc le fibers to oxidative dysfunction, and may even play a role as a sign aling molecule for mitochondrial proliferation.