Tier 3 — preclinical

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 2023 42(11):113436

Bibliography

PubMed
PMID 37952157
PubMed Central
PMC10841857
DOI
10.1016/j.celrep.2023.113436
Funding
NIH R01 AG077536; University of Washington Nathan Shock Center P30 AG013280 pilot support; San Antonio Nathan Shock Center P30 AG013319 pilot support; NIA T32 AG052374; NIH R35 122140
Competing interests
No competing interests declared.

Study snapshot

DesignPreclinical transgenic mouse study using skeletal-muscle-specific TFEB overexpression across aging and neurodegenerative disease models.
ModelAged and neurodegenerative/tauopathy mouse models with skeletal-muscle-specific TFEB overexpression.
SampleMultiple mouse cohorts; n varied by experiment
InterventionSkeletal-muscle-specific TFEB overexpression
DurationAge-dependent cohorts with chronic muscle-specific TFEB overexpression
EndpointsSkeletal muscle lysosomal and mitochondrial biology; Central nervous system neuroinflammation; Tau-associated neuropathology; Brain transcriptional remodeling; Cognition and memory

What the study showed, in plain terms

In transgenic mice, skeletal-muscle-specific TFEB overexpression improved muscle lysosomal and mitochondrial biology and was associated with less central nervous system neuroinflammation and tau-related pathology, brain transcriptional remodeling, and preservation of cognition and memory during aging and neurodegenerative disease. This is mechanistic animal evidence for muscle-to-brain signaling, not evidence that an oral TFEB-targeting compound such as PS18 produces the same effects.

Key findings

Enhancing TFEB signaling specifically in skeletal muscle produced systemic effects that reached the brain, including reduced neuroinflammatory signaling and tau-associated pathology and preservation of cognitive function in mouse models. The work supports a biologically plausible muscle-to-brain axis involving TFEB.

What this study can and cannot tell us

This is preclinical mouse evidence based on genetic TFEB overexpression. Genetic overexpression is not equivalent to pharmacologic TFEB activation, the study did not test PS18 or a DoNotAge formulation, and the results cannot be assumed to translate to humans. Several analyses also showed sex-dependent biology.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology