Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease

Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders. [Display omitted] •Increased TFEB expression modifies aging hallmarks in skeletal muscle•Muscle-TFEB reduces neuroinflammation during aging and neurodegeneration•Neuroprotective muscle-to-brain signaling is activated in a sex-biased manner Matthews et al. demonstrate that activation of the muscle-to-brain axis in vivo promotes robust neuroprotective effects during aging and neurodegenerative disease. These benefits are associated with transcriptional remodeling of the hippocampus and sex-biased modulation of classical pathways known to decline with age, including synaptic plasticity, mitochondrial function, and ribosomal metabolism.