Satellite cells—also known as muscle stem cells—normally stay dormant but activate to repair muscle after injury. When their function declines with age or diseases like muscular dystrophy, satellite cells decrease in number or lose their ability to divide, leading to muscle degeneration.
Although many studies track how these cells regenerate muscle, they rarely examine the signals that trigger satellite cells to activate. This week in Nature Communications a Stanford research team reports that immune cells play an unexpected role in switching satellite cells into repair mode.
Funded in part by CIRM, this study offers key insights into muscle regeneration and could guide the development of new treatments for muscle disorders.
ADAMTS1: a muscle injury signal?
To reach this conclusion, the team built on earlier studies showing that the gene Adamts1 is more active in satellite cells after injury than in dormant cells. Because ADAMTS1 is a secreted protein, the researchers suspected it might act as a signal that activates satellite cells. When they applied ADAMTS1 to mouse muscle fibers in a dish, the satellite cells activated.
Next, they examined ADAMTS1 in a mouse model of muscle injury and saw the protein rise sharply within one day. This timing matched the point when satellite cells leave dormancy and begin dividing to form new muscle. However, follow‑up tests showed that satellite cells were not producing ADAMTS1. Instead, macrophages—a type of white blood cell—generated the protein at the injury site.
Macrophages, whose name means “big eaters,” patrol tissues, remove dead cells, and fight infection. They also secrete proteins that alert the immune system. In this case, they appear to send the signal that wakes satellite cells and starts muscle repair.
Immune cell’s double duty
To confirm the macrophages’ additional role as the transmitter of this ADAMTS1 muscle injury signal, the researchers generated transgenic mice whose macrophages produce abnormally high levels of ADAMTS1. The activation of satellite cells in these mice was much higher than in normal mice lacking this boost of ADAMTS1 production. And four months after birth, the increased activation led to larger muscles in the transgenic mice. In terms of muscle regeneration, one-month old transgenic mice recovered from muscle injury faster than normal mice. Stanford professor Brian Feldman, MD, PhD, the senior author of the study, described his team’s initial reaction to their findings in an interview with Scope, Stanford Medicine’s blog:
“While, in retrospect, it might make intuitive sense that the same cells that are sent into a site of injury to clean up the mess also carry the tools and signals needed to rebuild what was destroyed, it was not at all obvious how, or if, these two processes were biologically coupled. Our data show a direct link in which the clean‑up crew releases a signal to launch the rebuild. This was a surprise.”
Further experiments showed how ADAMTS1 sends that signal. The protein cuts a molecule called NOTCH on the surface of satellite cells. NOTCH normally tells satellite cells to stay dormant. When ADAMTS1 degrades NOTCH, it lifts that dormancy and allows the cells to divide and mature into muscle cells.
A pathway to novel muscle disorder therapies?
“While, in retrospect, it might make intuitive sense that the same cells that are sent into a site of injury to clean up the mess also carry the tools and signals needed to rebuild what was destroyed, it was not at all obvious how, or if, these two processes were biologically coupled. Our data show a direct link in which the clean‑up crew releases a signal to launch the rebuild. This was a surprise.”
Further experiments revealed how ADAMTS1 delivers that signal. The protein cuts a molecule called NOTCH on the surface of satellite cells. NOTCH normally keeps satellite cells dormant. When ADAMTS1 degrades NOTCH, it lifts that dormancy and allows the cells to divide and mature into muscle cells.