The Toll of Aging on the Quest for Gold
Although the summer Olympics are over for another four years, the world is again amazed at the amount of training these Herculean athletes endure in order to capture gold. A young body usually recovers quite easily after an intense training session; thus, permitting young athletes to continue their quest. However, age inevitably starts to take its toll on the body. Repairing damaged muscles becomes increasingly more difficult with advancing age, though “why” the ability to regenerate muscle is lost is largely unknown. To try to figure it out, a research group led by Jerome Feige and C. Florian Bentzinger at the Nestlé Institute of Health Sciences decided to look the effects of age on muscle stem cells, in the context of their normal contribution to muscle regeneration.
The research group started with comparing gene expression in muscle stem cells from young and old mice. They found that the cells from the injured old mice showed lower expression of genes involved in the cell cycle regulation, higher expression of JAK-STAT and MAP kinase pathway-associated genes (major cell signaling pathways for a variety of functions), and multiple changes in the gene expression for proteins associated with the extracellular matrix (ECM) receptor pathway. The ECM findings were of particular interest, suggesting a role for ECM in muscle regeneration.
To confirm the ECM’s contribution to the muscle regeneration, the group used the SOMAscan® assay to directly measure and compare changes in protein levels in homogenized muscles from injured or uninjured, and young or old mice. They found that many ECM proteins showed higher levels in the old uninjured mice, an observation that is consistent with the usual increase in fibrosis seen in aging muscles. However, when looking at the injured mice, they saw that, in young mice, elevated levels of fibronectin occurred quickly after injury. However, in the old injured mice there was significantly less fibronectin present.
Upon further investigation, the overall importance of fibronectin in regenerating injured muscles solidified. Originating predominantly from lineage-positive cells (stem cells expressing markers seen in mature cells) near the sites of injury, fibronectin serves as an ideal substrate for muscle stem cells to adhere. The researchers found that loss of this ideal substrate led to alterations in several signaling cascades, in line with previous observations from other groups. These alterations may contribute to the aged muscle cells’ increased susceptibility to anoikis (cell-death induced by failure to anchor onto matrix).
Digging even deeper, the investigators looked into the role of a protein called focal adhesion kinase (FAK), which they noted is a known inhibitor of anoikis and dependent on fibronectin for activation. Like fibronectin, they observed the FAK levels to decrease with age in muscle stem cells, which may account for the increased susceptibility of the aged muscle stem cells to anoikis.
Is fibronectin the key to the fountain of youth for aged muscle stem cells? The researchers saw that aged muscle stem cells showed improved adhesion to matrices that included fibronectin, which reduced the cells’ susceptibility to anoikis and slightly improved their proliferation. The inclusion of fibronectin in the matrix also restored the FAK activity and subcellular localization in the aged muscle stem cells. When the researchers injected injured old mice with fibronectin, they saw more FAK in cells undergoing myogenesis, and the localization of the FAK within the cells was comparable to that of cells from young mice. In addition to the improved signaling, the researchers saw improved proliferation of the cells that would go on to become muscle cells. The resulting muscle fibers indeed showed fewer immature muscle fibers than seen in control mice, suggesting that the effects of age on muscle regeneration were mitigated by injection of fibronectin.
For the aging Olympian athletes, fibronectin injections would probably be seen as a new form of doping. For the rest of the aging populace, however, increasing fibronectin may be the winner as a way to maintain a more active lifestyle well into “old” age.
Link to paper: http://rdcu.be/i9ib (Lukjanenko et al., 2016)
Lukjanenko, L., Jung, M. J., Hegde, N., Perruisseau-Carrier, C., Migliavacca, E., Rozo, M., . . . Bentzinger, C. F. (2016) Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice. Nat Med. doi:10.1038/nm.4126