Skeletal muscle TFEB overexpression transcriptionally remodels the mouse hippocampal landscape throughout lifespan in a sex-dependent manner [RNA-seq]

Skeletal 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. We generated a novel transgenic mouse that has overexpression of Transcription Factor E-B (TFEB), a master regulator of proteostasis and lysosomal function, in skeletal muscle. We discovered that the resulting changes in muscle function promotes transcriptional remodeling of the aging CNS, as well as preserves cognition and memory in aging mice. Our results implicate the maintenance of autophagic skeletal muscle signaling throughout aging to the 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. Overall design: mice with overexpression of Transcription Factor EB in skeletal muscle tissue were examined for age-associtated gene expression profile changes in the hippocampus compared to age and sex-matched littermate controls (no skeletal muscle TFEB overexpression) to further comprehend the muscle-to-brain axis implicated in age-related cognitive decline. Gene expression profiling by high-throughput sequencing for hippocampi of 6-month and 24-month, mice with skeletal muscle Transcription Factor EB overexpression and wild-type controls. Profiles for both male and female mice were generated