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

Ian Matthews, Allison Birnbaum, Anastasia Gromova, Amy W. Huang, Kailin Liu, Eleanor A. Liu, Kristen Coutinho, Megan McGraw, Dalton C. Patterson, Macy T. Banks, Amber C. Nobles, Nhat Nguyen, Gennifer E. Merrihew, Lu Wang, Eric Baeuerle, Elizabeth Fernandez, Nicolas Musi, Michael J. MacCoss, Helen C. Miranda, Albert R. La SpadaConstanza J. Cortes

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number113436
JournalCell Reports
Volume42
Issue number11
DOIs
StatePublished - Nov 28 2023

Keywords

  • CP: Neuroscience
  • TFEB
  • aging
  • brain
  • exercise
  • muscle
  • neurodegeneration
  • tau

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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