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

doi:10.1016/j.celrep.2023.113436

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

Cell Rep. 2023 Nov 28;42(11):113436. doi: 10.1016/j.celrep.2023.113436. Epub 2023 Nov 11.

Authors

Ian Matthews¹, Allison Birnbaum¹, Anastasia Gromova², Amy W Huang¹, Kailin Liu¹, Eleanor A Liu¹, Kristen Coutinho³, Megan McGraw⁴, Dalton C Patterson⁴, Macy T Banks⁴, Amber C Nobles⁵, Nhat Nguyen², Gennifer E Merrihew⁶, Lu Wang⁷, Eric Baeuerle⁸, Elizabeth Fernandez⁸, Nicolas Musi⁹, Michael J MacCoss⁶, Helen C Miranda¹⁰, Albert R La Spada¹¹, Constanza J Cortes¹²

Affiliations

¹ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA.
² Department of Pathology and Laboratory Medicine, UCI Institute for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA.
³ Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁴ Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁵ Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁶ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
⁷ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
⁸ 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.
⁹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰ 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.
¹¹ 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. Electronic address: alaspada@uci.edu.
¹² Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90007, USA. Electronic address: cjc_149@usc.edu.

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.

Keywords: CP: Neuroscience; TFEB; aging; brain; exercise; muscle; neurodegeneration; tau.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aging
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Central Nervous System
Mice
Mice, Transgenic
Muscle, Skeletal
Neurodegenerative Diseases*
Neuroinflammatory Diseases
Transcription Factors

Substances

Transcription Factors
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding