Muscle TFEB Overexpression Slows Cognitive Aging in Mice

Muscle tissue is metabolically active, and affects the operation of other organs. At this time, a good map of the important signals that pass between muscle and other tissues has yet to be created. Maintenance of muscle mass and function in later life clearly produces a more systemic benefit than simply postponing weakness and frailty, but the details of the biochemistry are not well understood. Thus researchers can perform muscle-specific interventions in animal models, such as the one noted here, show a slowing of cognitive aging to result from that intervention, but not have a good grasp of how exactly how the altered muscle tissue influences the brain in this case.

Over the last decade, growing evidence has suggested that the periphery contributes to the etiology of age-associated neurodegenerative diseases. Manipulation of skeletal muscle protein quality control pathways protects against the accumulation of aggregation-prone disease proteins in the invertebrate brain and retina. The mechanisms responsible for these benefits remain poorly understood, some of these effects are mediated by secreted factors that communicate metabolic and inflammatory signals between tissues. Although the source and identity of these neuroprotective circulating cytokines are unclear, several are known to be secreted from skeletal muscle, an unconventional endocrine organ that secretes a myriad of bioactive factors that induce metabolic changes in distant tissues such as liver, adipose tissue, and the central nervous system (CNS).

Skeletal muscle metabolism is regulated in part by transcription factor E-B (TFEB), a master regulator of the lysosomal-to-nucleus signaling that integrates cellular metabolism and lysosomal function. TFEB expression and function are strongly induced in skeletal muscle in response to interventions with neuroprotective effects against aging and neurodegenerative disease, including low nutrient conditions and exercise. TFEB controls muscle metabolic flexibility during exercise, inducing the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation.

Here, we report the generation of a transgenic mouse with enhanced muscle metabolism via lifelong overexpression of TFEB. The resulting enhanced TFEB signaling protects against the onset of age-associated mitochondrial dysfunction in aging skeletal muscle. Overexpression of TFEB in skeletal muscle significantly reduces hippocampal accumulation of neuropathological hallmarks and reduces neuroinflammation in a mouse model of tauopathy, despite no exogenous activation of the transgene in the CNS. Muscle TFEB overexpression ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the "healthy" aged CNS, preserving cognitive performance in aging mice. Our results implicate maintenance of skeletal muscle function in regulating mammalian CNS health, and suggest that skeletal muscle-originating factors may act as therapeutic targets against age-associated neurodegenerative diseases.