Dataset Information

Skeletal Muscle TFEB Signaling Promotes Central Nervous System Function and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

ABSTRACT: Skeletal muscle has recently arisen as a novel 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 novel transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of Transcription Factor E-B (TFEB). We have discovered that the resulting geroprotective benefits in skeletal muscle reduces neuroinflammation and accumulation of tau-associated pathological hallmarks in a mouse model of tau pathology. Muscle TFEB overexpression also significantly ameliorates proteotoxicity, reduces neuroinflammation and promotes transcriptional remodeling of the aging CNS, preserving cognition and memory in aging mice. Our results implicate the maintenance of skeletal muscle function throughout aging to direct regulation of CNS health and disease, and suggest that skeletal-muscle originating factors may act as novel therapeutic targets against age-associated neurodegenerative disorders.

ORGANISM(S): Mus Musculus

SUBMITTER: Gennifer Merrihew

PROVIDER: PXD045241 | panorama | Wed Dec 06 00:00:00 GMT 2023

REPOSITORIES: PanoramaPublic

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

Matthews Ian I Birnbaum Allison A Gromova Anastasia A Huang Amy W AW Liu Kailin K Liu Eleanor A EA Coutinho Kristen K McGraw Megan M Patterson Dalton C DC Banks Macy T MT Nobles Amber C AC Nguyen Nhat N Merrihew Gennifer E GE Wang Lu L Baeuerle Eric E Fernandez Elizabeth E Musi Nicolas N MacCoss Michael J MJ Miranda Helen C HC La Spada Albert R AR Cortes Constanza J CJ

Cell reports 20231111 11

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 neuroin ...[more]

PMID: 37952157

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Project description:Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. ELAM is proposed to restore mitochondrial bioenergetic function by stabilizing inner membrane structure and increasing oxidative phosphorylation coupling and efficiency. Although ELAM treatment effectively attenuates physiological declines in multiple tissues in rodent aging models, it remains unclear whether these functional improvements correlate with favorable changes in molecular biomarkers of aging. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post- measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force are significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. However, at the level of gene expression and DNA methylation, ELAM did not produce statistically significant changes in molecular organization and biological age in most treatment groups. Pathway analyses indicated that ELAM treatment showed pro-longevity shifts in gene expression such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and heart failure in an aging mouse model, but that these functional improvements occur independently of changes in epigenetic and transcriptomic age. Thus, age-related changes in function may be uncoupled from changes in molecular biological age.

Dataset Information

Skeletal Muscle TFEB Signaling Promotes Central Nervous System Function and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

Publications

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

Similar Datasets

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