Medicine

Slowly healing aged muscle appears to lack beta 1 integrin in muscle stem cells — as well as fibronectin in the muscle itself — in mice

© 2016 Peter Free

Citation — to studies

Michelle Rozo, Liangji Li, and Chen-Ming Fan, Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice, Nature Medicine, DOI: 10.1038/nm.4116 (advance online publication, 04 July 2016)

Laura Lukjanenko, M Juliane Jung, Nagabhooshan Hegde, Claire Perruisseau-Carrier, Eugenia Migliavacca, Michelle Rozo, Sonia Karaz, Guillaume Jacot, Manuel Schmidt, Liangji Li, Sylviane Metairon, Frederic Raymond, Umji Lee, Federico Sizzano, David H Wilson, Nicolas A Dumont, Alessio Palini, Reinhard Fässler, Pascal Steiner, Patrick Descombes, Michael A Rudnicki, Chen-Ming Fan, Julia von Maltzahn, Jerome N Feige, and C Florian Bentzinger, Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice, Nature Medicine, DOI: 10.1038/nm.4126 (advance online publication, 04 July 2016)

Citation — to press release

Carnegie Science, Why Do Aged Muscles Heal Slowly?, Carnegie Institution for Science (04 July 2016)

A therapeutic clue to healing?

From Carnegie Institution for Science:

[O]ur results show that aged muscle stem cells with compromised b1-integrin activity and aged muscles with insufficient amount of fibronectin [are] both root causes of muscle aging. This makes b1-integrin and fibronectin very promising therapeutic targets,” [Chen-Ming] Fan said.

© 2016 Carnegie Science, Why Do Aged Muscles Heal Slowly?, Carnegie Institution for Science (04 July 2016)

In science-ese — for those who understand how cellular signaling works

From the abstract of the first listed paper:

Augmenting β1-integrin activity with a monoclonal antibody restores Fgf2 sensitivity and improves regeneration after experimentally induced muscle injury.

The same treatment also enhances regeneration and function of dystrophic muscles in mdx mice, a model for Duchenne muscular dystrophy.

Therefore, β1-integrin senses the [satellite cell] niche [— meaning the cellular microenvironment —] to maintain responsiveness to Fgf2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised.

© 2016 Michelle Rozo, Liangji Li, and Chen-Ming Fan, Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice, Nature Medicine, DOI: 10.1038/nm.4116 (advance online publication, 04 July 2016) (at Abstract) (extracts)

And from the second abstract:

Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs).

Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers.

By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche.

Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.

© 2016 Laura Lukjanenko, M Juliane Jung, Nagabhooshan Hegde, Claire Perruisseau-Carrier, Eugenia Migliavacca, Michelle Rozo, Sonia Karaz, Guillaume Jacot, Manuel Schmidt, Liangji Li, Sylviane Metairon, Frederic Raymond, Umji Lee, Federico Sizzano, David H Wilson, Nicolas A Dumont, Alessio Palini, Reinhard Fässler, Pascal Steiner, Patrick Descombes, Michael A Rudnicki, Chen-Ming Fan, Julia von Maltzahn, Jerome N Feige, and C Florian Bentzinger, Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice, Nature Medicine, DOI: 10.1038/nm.4126 (advance online publication, 04 July 2016) (at Abstract) (paragraph split)

The moral? — Humans may work the same way

But even if we do, whether the promised therapeutic targets will pan out remains questionable. Aging implies a host of cellular and physiologically systemic changes. Just throwing in some missing or depleted ingredients seems unlikely to bridge the entirety of aging’s diminished or absent function.