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Small Molecule Mediated Intervention of NF-kB or TGF-β Signaling Reverses Age-Related Phenotypes in Satellite Cells and Enhances Muscle Repair

42 Pages Posted: 6 Sep 2018 Sneak Peek Status: Review Complete

See all articles by Massimiliano Cerletti

Massimiliano Cerletti

Harvard University - Department of Stem Cell and Regenerative Biology

Tata Nageswara Rao

Harvard University - Department of Stem Cell and Regenerative Biology

Deepti A. Cole

Joslin Diabetes Center - Bioinformatics Core

John T. Moore

GlaxoSmithKline - Target and Pathway Validation Unit

Tsu T. Chuang

GlaxoSmithKline - Regenerative Medicine Discovery Performance Unit

Dave J. Becherer

GlaxoSmithKline - Metabolism Discovery Performance Unit

Lauren R. Sheckler

GlaxoSmithKline - Metabolism Discovery Performance Unit

Stephen A. Stimpson

GlaxoSmithKline - Metabolic Pathways and Cardiovascular Therapeutic Area Unit

Joshua J. Schroeder

Joslin Diabetes Center - Genomics Core

Matthew A. Inlay

Stanford University - Institute for Stem Cell Biology and Regenerative Medicine

Derrick J. Rossi

Harvard University - Department of Stem Cell and Regenerative Biology

Irving L. Weissman

Stanford University - Institute for Stem Cell Biology and Regenerative Medicine

Amy J. Wagers

Harvard University - Department of Stem Cell and Regenerative Biology

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Abstract

Skeletal muscle normally exhibits robust regenerative potential in youth; however, myogenic activity declines with age, resulting in defective muscle repair after injury. In this study, we identified signaling pathways in mouse muscle stem cells that are altered with aging and contribute to age-dependent decline in muscle regenerative potential. By analyzing the transcriptional profile of highly purified muscle satellite cells, we identified a unique set of genes whose expression changes with chronological time. This set contains genes regulating inflammatory processes, cell adhesion and matrix interactions, proteolysis, extracellular matrix remodeling, skeletal muscle development, cancer and connective tissue disorders. Ingenuity Pathway Analysis (IPA) of these transcripts indicated a central role for the NF-κB pathway in muscle satellite cell dysfunction. In addition, we noted altered expression of extracellular matrix genes, a signature that could be linked to changes in TGF-β-like signaling activity. Pharmacological modulation of either the NF-κB or TGF-β-like signaling pathways with small molecule inhibitors targeting IKK2 kinase or ALK4/5 receptor-like kinase enhanced regenerative potential in aged muscle, altering both the kinetics and magnitude of the response. These results identify key pathways underlying age-related muscle dysfunction and demonstrate the potential therapeutic relevance of small molecules that target them.

Suggested Citation

Cerletti, Massimiliano and Rao, Tata Nageswara and Cole, Deepti A. and Moore, John T. and Chuang, Tsu T. and Becherer, Dave J. and Sheckler, Lauren R. and Stimpson, Stephen A. and Schroeder, Joshua J. and Inlay, Matthew A. and Rossi, Derrick J. and Weissman, Irving L. and Wagers, Amy J., Small Molecule Mediated Intervention of NF-kB or TGF-β Signaling Reverses Age-Related Phenotypes in Satellite Cells and Enhances Muscle Repair (September 5, 2018). Available at SSRN: https://ssrn.com/abstract=3244794 or http://dx.doi.org/10.2139/ssrn.3244794
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Massimiliano Cerletti (Contact Author)

Harvard University - Department of Stem Cell and Regenerative Biology ( email )

7 Divinity Avenue
Cambridge, MA 02138
United States

Tata Nageswara Rao

Harvard University - Department of Stem Cell and Regenerative Biology

7 Divinity Avenue
Cambridge, MA 02138
United States

Deepti A. Cole

Joslin Diabetes Center - Bioinformatics Core

One Joslin Place
Boston, MA
United States

John T. Moore

GlaxoSmithKline - Target and Pathway Validation Unit

5 Moore Dr
RTP, NC 27709
United States

Tsu T. Chuang

GlaxoSmithKline - Regenerative Medicine Discovery Performance Unit

Stockley Park West
Uxbridge, Middlesex UB11 1BT
United Kingdom

Dave J. Becherer

GlaxoSmithKline - Metabolism Discovery Performance Unit

5 Moore Dr
RTP, NC 27709
United States

Lauren R. Sheckler

GlaxoSmithKline - Metabolism Discovery Performance Unit

5 Moore Dr
RTP, NC 27709
United States

Stephen A. Stimpson

GlaxoSmithKline - Metabolic Pathways and Cardiovascular Therapeutic Area Unit

5 Moore Dr
RTP, NC 27709
United States

Joshua J. Schroeder

Joslin Diabetes Center - Genomics Core

One Joslin Place
Boston, MA 02115
United States

Matthew A. Inlay

Stanford University - Institute for Stem Cell Biology and Regenerative Medicine

Stanford, CA 94305
United States

Derrick J. Rossi

Harvard University - Department of Stem Cell and Regenerative Biology

7 Divinity Avenue
Cambridge, MA 02138
United States

Irving L. Weissman

Stanford University - Institute for Stem Cell Biology and Regenerative Medicine

Stanford, CA 94305
United States

Amy J. Wagers

Harvard University - Department of Stem Cell and Regenerative Biology ( email )

7 Divinity Avenue
Cambridge, MA 02138
United States

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