Pathologically, multiple sclerosis (MS) can be identified by the presence of diffuse, discrete demyelinated areas, called plaques. Demyelination is a major feature of MS and therefore, an approach to the management of MS involves an increase in remyelination of axons, resulting in clinical improvement. Peroxisome proliferator-activated receptor ? or ? (PPAR?) being highly expressed in the CNS participates in many brain functions including myelination. Being a nuclear hormone receptor, PPAR? needs ligand(s) for its activation and nuclear translocation. Therefore, identification of new nontoxic ligand of PPAR? would be very important for promoting remyelination. The ?-hydroxy ?-methylbutyrate (HMB) is available in local GNC stores as a muscle-building supplement in human. It is a physiological molecule that is produced in human through the metabolism of L-leucine. HMB is known to increase exercise-induced gains in muscle size and muscle strength and improve exercise performance. Here, we will test an exciting hypothesis that HMB binds to the ligand-binding domain of PPAR? (Specific aim I) and that HMB and its precursor L-leucine promote maturation of OPCs (Specific aim II) and stimulate remyelination in animal models (cuprizone and experimental autoimmune encephalomyelitis or EAE) of CNS demyelination (Specific aim III) via OPC-specific and/or microglia-specific PPAR?. To investigate whether the muscle building effects of L-leucine and HMB could contribute to improved motor function in cuprizone and EAE models, Specific aim III will also examine the role of skeletal muscle-specific PPAR?. A positive outcome of this cutting-edge R01 proposal will delineate easily available muscle-building supplement HMB as a physiological ligand of PPAR? and enhance the possibility of promoting remyelination and treating patients with MS and other demyelinating disorders with HMB and its precursor L-leucine as primary or adjunct therapy.
Promoting remyelination is an important area of research. Here, we will test a novel idea that muscle building supplement HMB binds to peroxisome proliferator-activated receptor ? (PPAR?) and that HMB and its precursor L-leucine, an essential amino acid, promote maturation of oligodendroglial progenitor cells and stimulate remyelination in animal models of demyelination via PPAR?. This study will enhance the possibility of promoting remyelination and treating patients with multiple sclerosis and other demyelinatingdisorders with L-leucine and its metabolite HMB as primary or adjunct therapy. 1