Muscles make up nearly 40% of the human body and power every move we make, from a child’s first steps to recovery after injury. For some, however, muscle development goes awry, leading to weakness, delayed motor milestones or lifelong disabilities.
New research from the University of Georgia is shedding light on why.
UGA researchers have created a first-of-its-kind CRISPR screening platform for human muscle cells, identifying hundreds of genes critical to skeletal muscle formation and uncovering the potential cause of a rare genetic disorder. The findings come from two companion papers published in Nature Communications, one describing the large-scale screen and a second digging into a particular gene’s role in muscle development.
This is the first time people can have this power to study thousands of genes in muscles in a single experimental run.
Pengpeng Bi, Complex Carbohydrate Research Center
Together, the studies provide a comprehensive genetic map of how human muscle fibers are built and lend insights into the effects of genetic mutations on developmental muscle defects. By linking specific genes to the muscle-building process, this genetic roadmap gives clinicians a practical shortlist to more quickly pinpoint the likely genetic causes of a patient’s muscle-development disorder. It also provides researchers with clear targets to prioritize future drug or gene therapy approaches.
“This is the first time people can have this power to study thousands of genes in muscles in a single experimental run,” said Pengpeng Bi, lead author of the studies and an associate professor in UGA’s Complex Carbohydrate Research Center and the UGA Center for Molecular Medicine. “Previously, this could be done in mice or maybe in fish, but, even with genetic similarities, there are many distinguishing characteristics of human muscle cells.”
New CRISPR screen identifies 250 genes essential to human muscle development
Skeletal muscle forms through a process called myoblast fusion, in which thousands of individual cells merge to form a single muscle fiber. This process is fundamental to human muscle development and regeneration. When it fails, it can lead to weak, underdeveloped or nonfunctional muscles.
Despite its importance, myoblast fusion has been difficult to study in humans. Most previous discoveries were in animal models, which don’t fully capture the complexity of human biology. To overcome this limitation, UGA researchers developed a CRISPR screening platform tailored to humans.
The screen identified 250 genes that are essential in human myoblast fusion. Most of these genes have never been functionally linked to muscle development in any species. Comparing results to existing large clinical databases, researchers found that mutations in 41of the genes correlate to skeletal muscle development defects.
Now, once a doctor sees a patient with developmental defects, they … have a robust roadmap to pinpoint abnormalities that could be the underlying cause.
Pengpeng Bi
While Bi cautioned that the study did not uncover a direct causal relationship, he likened it to a mechanic understanding the function of each part of a car.
“Before a mechanic can repair a car, they need to know how it works,” he said. “How do you change the oil? Where is the engine? What are the different parts?
“Now, once a doctor sees a patient with developmental defects, they can do genetic testing and have a robust roadmap to pinpoint abnormalities that could be the underlying cause.”
After which, he said, new genetic therapies or drugs could be engineered to address the developmental challenge.
Screen uncovers why CHAMP1 mutations cause developmental disorders in children
One gene specifically identified by the screen, CHAMP1, became the focus for a second study.
CHAMP1 mutations are known to cause a rare childhood disorder characterized by developmental delay, low muscle tone and muscle weakness. Although the condition had been recognized by clinicians for years, the biological foundations of the CHAMP1 gene in muscle cells were previously unknown.
The new study revealed that CHAMP1 plays a direct role in muscle development. The gene helps a key protein that controls muscle genes turn on another important protein called Myomaker, which muscles need for cell fusion.
To confirm the finding, researchers examined muscle cells from patients with CHAMP1 mutations. These cells struggled to fuse and produced much less Myomaker than normal. When scientists restored Myomaker levels, the muscle cells were able to fuse effectively again.
“This study provides a clear mechanistic explanation for why CHAMP1 mutations cause muscle symptoms,” said Bi, noting that the study was conducted in close collaboration with the CHAMP1 Research Foundation and patient families. “Partnerships between scientists and the communities they serve are integral to our success. Although only a few hundred CHAMP1 patients are known worldwide, the impact on affected families is profound.”
The insights from these studies could have future application in studies of other genetic disorders, muscle regeneration, aging or injury repair.
“There’s a lot to learn,” Bi said. “But these studies have given us a powerful resource to understand human muscle development and how that process can break down.”