by Tim Bonfield
Examine a fully formed muscle cell under a microscope and even untrained eyes can see a striking feature. Unlike most other cells in our skin, bones, organs and blood, muscle cells are elongated structures that have not one, but multiple nuclei.
Biologists have understood for many years that muscle cells possess the unusual ability to fuse together as they develop into the fibrous strands that put our skeletons into motion. But only recently have scientists begun to unlock the genetic secrets of the fusion process, an advance that could have extensive implications for health.
Dr. Doug Millay says understanding the machinery of muscle cell fusion could open the door to new treatments for a number of muscle-wasting conditions, ranging from Duchenne muscular dystrophy to cancer to the natural aging process.
While working as a post-doctoral fellow at the University of Texas Southwestern in Dallas, Doug Millay, PhD, and his mentor found the first muscle-specific gene shown to play an essential role in embryonic muscle cell fusion. In a paper published in 2013 in Nature, they dubbed the gene “myomaker.” Then in a 2014 follow-up paper in Genes and Development, the team showed that the myomaker gene also is necessary for normal adult muscle cell regeneration.
Now Millay works at Cincinnati Children’s, returning to his hometown and to the institution where he previously trained, to continue exploring the implications of the myomaker gene. His work received a major boost this summer when he became one of about 20 outstanding young researchers nationwide to be named a Pew Scholar.
GENOME SEARCH PRODUCES RESULTS
Millay says they found the myomaker gene by extending concepts he learned working as a graduate student at Cincinnati Children’s in the laboratory of Jeffery Molkentin, PhD, a Howard Hughes Medical Institute (HHMI) investigator in the Division of Molecular and Cardiovascular Biology.
“Jeff had been working on how calcium regulates aspects of heart development and disease,” Millay says. “We took some of the observations from his work on the heart and asked similar questions in skeletal muscle, so this experience was the foundation for my future work on skeletal muscle.”
Millay and colleagues searched available databases for genes explicitly expressed in skeletal muscle. They found about 30 gene candidates, some of which had been well annotated with descriptions of their functions, while others had incomplete annotations. Myomaker was among the incompletely annotated genes on the list.
Further testing revealed that, unlike other genes on the candidate list, myomaker was crucial for normal muscle cell formation. That finding implies that it may be possible to restore normal muscle function by introducing a “normal” myomaker gene to muscle stem cells that lack the gene or have a malfunctioning version.
Once the team determined that myomaker plays an essential role in normal development, they made another vital observation.
GENE CAN HITCH RIDES ON NON-MUSCLE CELLS
The myomaker gene is not found in cardiac muscle nor in the smooth muscles that drive other organ functions. However, in mice, the gene can be expressed on non-muscle cells, which then allows these cells to fuse to skeletal muscle, Millay has learned.
This implies that myomaker might be useful as a delivery vehicle for future therapeutic approaches to specifically target muscle cells.
Millay cautions, however, that myomaker appears to be only one part of the machinery of muscle cell development. Other yet-to-be-defined elements may have even more value as potential therapy targets. Also, the gene manipulations that researchers can do with mice may not be possible in humans.
“We still have much work to do to understand the feasibility of this approach. We are a ways off from clinical applications,” Millay says.
MUSCULAR DYSTROPHY IMPLICATIONS AND MORE
Even so, the implications are intriguing.
“If we can understand the machinery of how muscle cells fuse, then we eventually might be able to manipulate that process in a disease setting,” Millay says.
One possibility that immediately jumps to mind among pediatric medical researchers is Duchenne muscular dystrophy, along with similar genetic diseases that gradually erode muscle function.
“Boys with Duchenne have a mutation in a gene called dystrophin, which results in muscle weakness but these muscle still harbor multiple-but-defective nuclei,” Millay says. “So one question is, would it be possible to use myomaker to deliver functional nuclei and a normal copy of dystrophin to those cells to help the muscles retain their function?”
If muscle function can be restored or preserved in muscular dystrophies, the next question would be could muscle loss be reversed in other, more common conditions such as cancer, AIDS, COPD, or even the natural aging process? And what would restoring muscle function mean?
“In all of these conditions, muscle loss reduces the quality of life,” Millay says. “But restoring muscle cell growth may likely do even more than impact quality of life. It could also slow the progression of the disease itself.”