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

Cell Reports (Nov 2023)

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

Journal volume & issue: Vol. 42, no. 11
p. 113436

Abstract

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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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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