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 Spada,
Constanza J. Cortes
Affiliations
Ian Matthews
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA
Allison Birnbaum
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA
Anastasia Gromova
Department of Pathology and Laboratory Medicine, UCI Institute for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA
Amy W. Huang
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA
Kailin Liu
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA
Eleanor A. Liu
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA
Kristen Coutinho
Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Megan McGraw
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Dalton C. Patterson
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Macy T. Banks
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Amber C. Nobles
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Nhat Nguyen
Department of Pathology and Laboratory Medicine, UCI Institute for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA
Gennifer E. Merrihew
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Lu Wang
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA
Eric Baeuerle
Department of Pharmacology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Network, San Antonio, TX 78229, USA
Elizabeth Fernandez
Department of Pharmacology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Network, San Antonio, TX 78229, USA
Nicolas Musi
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Michael J. MacCoss
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Helen C. Miranda
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; RNA Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Albert R. La Spada
Department of Pathology and Laboratory Medicine, UCI Institute for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA; Department of Neurology and Department of Biological Chemistry, UCI Institute for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA; Corresponding author
Constanza J. Cortes
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA; Corresponding author
Summary: 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.
