Enhanced skeletal muscle proteostasis as a determinant of CNS protein quality control and neural function in the aging brain
The importance of proteostasis to health and disease is well documented, yet how this process is regulated in a whole organism context remains poorly understood, especially in mammals. Individual organs in the body, particularly skeletal muscle, may play a pivotal role in regulating proteostasis in other tissues; hence, this project investigates the role of skeletal muscle-expressed Transcription factor E-B (TFEB), a master transcription factor regulator of autophagy and cellular clearance, in promoting CNS proteostasis during aging. These studies will address muscle-to-brain cell-non autonomous proteostasis signaling, determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection, uncover the mechanistic basis for this effect, develop powerful new models for testing
mitophagy/autophagy activity in the aging CNS, and establish if soluble factors secreted by muscle (“myokines”) mediate beneficial CNS effects in conditional skeletal muscle-expressing TFEB transgenic mice, in the hope that such work may yield therapeutic opportunities for promoting CNS quality control pathways and function in age-related brain diseases.
September 15, 2017 - September 14, 2022