Muscle building supplement HMB for remyelination

病理上，多发性硬化症（MS）可以通过弥漫性、离散性脱髓鞘区（称为斑块）的存在来鉴别。脱髓鞘是多发性硬化症的主要特征，因此，多发性硬化症的治疗方法包括增加轴突的髓鞘再生，从而改善临床。过氧化物酶体增殖体激活受体β或δ (PPARβ)在中枢神经系统中高度表达，参与包括髓鞘形成在内的许多脑功能。PPARβ是一种核激素受体，其激活和核易位需要配体。因此，鉴定新的无毒PPARβ配体对促进髓鞘再生具有重要意义。β-羟基β-甲基丁酸盐（HMB）在当地GNC商店可以买到，作为一种人体肌肉增强补充剂。它是人体通过l -亮氨酸代谢而产生的一种生理分子。众所周知，HMB可以增加运动引起的肌肉大小和肌肉力量的增加，并改善运动表现。在这里，我们将验证一个令人兴奋的假设，即HMB结合到PPARβ的配体结合域（Specific aim I）， HMB及其前体l -亮氨酸通过opc特异性和/或小胶质细胞特异性的PPARβ促进OPCs （Specific aim II）的成熟，并刺激中枢神经系统脱髓鞘（Specific aim III）的动物模型（铜酮和实验性自身免疫性脑脊髓炎或EAE）的再髓鞘形成。为了研究l -亮氨酸和HMB的肌肉构建作用是否有助于铜酮和EAE模型的运动功能改善，Specific aim III还将研究骨骼肌特异性PPARβ的作用。这项前沿R01提案的积极结果将描述易于获得的肌肉构建补充剂HMB作为PPARβ的生理配体，并增强HMB及其前体l -亮氨酸作为主要或辅助治疗促进髓鞘再生和治疗MS和其他脱髓鞘疾病患者的可能性。

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 β or δ (PPARβ) being highly expressed in the CNS participates in many brain functions including myelination. Being a nuclear hormone receptor, PPARβ needs ligand(s) for its activation and nuclear translocation. Therefore, identification of new nontoxic ligand of PPARβ would be very important for promoting remyelination. The β-hydroxy β-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 PPARβ (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 PPARβ. 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 PPARβ. A positive outcome of this cutting-edge R01 proposal will delineate easily available muscle-building supplement HMB as a physiological ligand of PPARβ 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.