Skeletal Muscle Proteostasis Promotes Central Nervous System Function and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

Abstract

ABSTRACTSkeletal muscle has recently arisen as a novel regulator of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Here we report the generation of a novel transgenic mouse with enhanced skeletal muscle proteostasis via targeted overexpression of Transcription Factor E-B, a master regulator of proteostasis and lysosomal function. We have discovered that the resulting enhanced muscle proteostasis function significantly ameliorates proteotoxicity, reduces neuroinflammation and promotes transcriptional remodeling of the aging CNS, preserving cognition and memory in aging mice. Enhancing skeletal muscle proteostasis also reduces neuroinflammation and accumulation of tau-associated pathological hallmarks in a mouse model of tau pathology. Our results implicate the maintenance of skeletal muscle proteostasis throughout aging to direct regulation of the CNS metabolism and function, and suggest that skeletal-muscle originating factors may act as novel therapeutic targets against age-associated neurodegenerative diseases.