Enhanced skeletal muscle proteostasis as a determinant of CNS protein quality control and neural function in the aging brain Cortes CJ1, Tucker HA1, Gromova A1,4, LA Spada AR1-3. Departments of Neurology1, Neurobiology2, Cell Biology3, Duke University School of Medicine, Biomedical Sciences Graduate Program, University of California San Diego4
Proteostasis is essential for cell health and viability, and involves complex and highly conserved networks that regulate protein translation, protein folding, and protein degradation. A decline in proteostasis function is one of the features of aging tissues, particularly of the central nervous system (CNS). Indeed, the aging brain is particularly sensitive to proteotoxic stress, as demonstrated by the high number of age-associated neurodegenerative disorders characterized by protein misfolding and aggregation, including Alzheimer's disease (AD). The regulation of non-cell autonomous proteostasis has recently arisen as a novel mechanism for the modulation of systemic homeostasis in worms and flies, and is postulated to have important organismal effects on metabolism and aging. However, to date, there are no studies addressing the existence and activity of these pathways in mammals, and their potential effects on the aging brain. Transcription Factor E-B (TFEB) is a powerful master transcription factor regulator of proteostasis, integrating autophagy and bioenergetics. We recently derived transgenic mice that moderately overexpress TFEB in skeletal muscle, and discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the CNS and also improve cognition and memory in aging mice. We have also uncovered changes in soluble TFEB muscle-secreted factors (myokines), suggesting a potential modulation of the observed neuroprotective effects. Identification of pathways regulating cross-talk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS.
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