Inhibition of signaling pathway stimulates adult muscle satellite cell function


Stem cell researcher Michael Rudnicki and his team from the University of Ottawa in Ontario, Canada has done it again. Rudnicki works on muscle stem cells and his work has greatly expanded our understanding of muscle satellite cells.

Muscle satellite cells are found in skeletal muscle, and they are a prime example of a “unipotent” stem cell, or a stem cell that can differentiate into only one cell type. Muscle satellite cells can only form skeletal muscle, but they can be isolated from skeletal muscle and grown in culture. When muscle is injured by exercise or shear forces, satellite cells move into action and divide to form muscle cells that fuse with existing muscle cells and firm them up. Lifting weights will also increase the activity of satellite cells and they will divide and contribute to the formation of new muscle fibers.

As we age, our capacity to regenerate damaged muscle slows way down. As someone who lifted weights in high school and then on and of after high school, I can attest to this as I have entered my later years. My joints get sore faster and I cannot handle heavier weights any more. Also, I do not get big from lifting anymore. This is due to the reduction in muscle repair and I have become older.

Rudnicki and others have identified a reduced capacity in adult mice to repair their muscles, and this reduction in muscle regenerative ability has been directly linked to reduced muscle satellite cell activity. Aged mice have muscle satellite cells that show a diminished ability to contribute to muscle regeneration and repopulate themselves.

In a recent paper published in the journal Nature Medicine, Rudnicki and his colleagues compared used gene expression profiles in the satellite cells of older and younger mice. Curiously, they identified the genes that encode the components of a cell signaling pathway called the “JAK-STAT” pathway that are more highly expressed in the satellite cells of older mice than in those of younger mice.

These data suggested that inhibition of the JAK-STAT pathway in the satellite cells of older mice might lead to higher satellite cell activity in older mice. Fortunately, there are drugs that will inhibit the JAK-STAT signaling pathway.

Knockdown of the activity of the Jak2 or Stat3 proteins significantly stimulated satellite stem cell divisions in culture (the satellite cells were grown in cultured muscles). When Jak2 of Stat3 were inhibited genetically (by introducing loss-of-function mutations in these genes), the isolated satellite cells showed a markedly ability to repopulate local satellite cell populations after they were transplanted into a wounded muscle.

Inhibition of Jak2 and Stat3 activity with drugs also stimulated the engraftment of satellite cells in a living animal. If these same rugs were injected into the muscle of older laboratory mice, these mice showed marked enhancement of muscle repair and force generation after injury.

Thus, these results from the Rudnicki lab show that they is an intrinsic property of satellite cells that separate the satellite cells of younger animals with those of older animals. These results also suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases.

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Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).