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Biology & Biomedical Sciences - Developing Muscles

Clarissa Henry

Basic biological research on zebrafish may lead to better treatment of human diseases and injuries

Staring into the crystal-clear plastic boxes inside the University of Maine’s zebrafish research facility, it can be difficult to focus on the movements of an individual fish. Both its stripes and its size make it hard to distinguish from its brethren in a population that is now more than 40,000 strong. The fish, on the other hand, seem to be very good at tracking the movements of an individual human, darting away in a flurry of fins and sinew at the slightest agitation.

At first glance, it seems as if the frightened fish simply bullet through the water, like tiny torpedoes propelled by some hidden, turbocharged motor. But closer observation reveals the true power behind their movements: a fluttering undulation of the body and tail, dependent, of course, on muscle.

With every flip of its fins, tiny bundles of skeletal muscle extend and contract in precisely coordinated synchrony, leveraging their movements against the fish’s miniature frame.

UMaine researcher Clarissa Henry has always been fascinated by the dynamic processes that shape the complex machinery of movement, and has pioneered a unique new system for studying how muscles and tendons develop inside the zebrafish. With a $1.28 million grant from the National Institutes of Health’s National Institute of Child Health and Human Development, Henry is shining a microscope-mounted light into the darkest corners of developmental biology, revealing new truths about embryonic processes that may lead to better treatment methods for conditions ranging from muscular dystrophy to tendinitis.

Henry’s current research, aimed at developing a better understanding of tendon formation and attachment in the embryo, is the next step in her pioneering efforts to describe the complexities of early development in vertebrates using zebrafish. Her previous research, funded by the Muscular Dystrophy Association, looked at how embryonic muscle cells transform from relatively stubby globs of cytoplasm into the long, multinucleated fibers of skeletal muscle in fully developed fry.

Skeletal muscles–from the orbicularis oculi to the gluteus maximus–are primarily responsible for movement in vertebrates, and abnormalities that arise during their formation can have dire consequences. For example, muscular dystrophy, one of the most common genetic diseases in humans, is characterized by a loss in muscular function that can manifest in many ways.

“One of the critical questions related to the treatment of muscular dystrophy is: How do humans make muscle during embryonic development?” says Henry. “We were able to make a significant step forward in this area because we were able to use an in vivo model. Prior to our work, no one was able to look into a live vertebrate embryo to see how muscle cells form at high resolution. We were able to do that with the zebrafish, thanks to the MDA.”

The strength of the preliminary data was one of the reasons NIH reviewers expressed such strong support for Henry’s latest project, pointing to her well-established methodology and the work’s potential benefits in the treatment of human disease. In addition to her obvious enthusiasm for the research, Henry has a technological advantage as well, utilizing cutting-edge equipment like a Zeiss ApoTome fluorescence microscope to peer inside the living embryo.

Like their plastic tanks, the developing eggs of the zebrafish are largely transparent, allowing researchers to observe and record changes in the cells as they happen, which is difficult or impossible in other vertebrate research models, such as mice or chickens. The zebrafish model has advantages over cell culture techniques as well, revealing important nuances in growth and development that can only be seen when cells form under the influence and constraints of a living organism.

With the help of the tiny zebrafish, Henry’s early work uncovered “a phenomenal amount of data” regarding muscle cell development, laying the foundation for further research related to tendon attachment and other processes. The new research path has already led Henry and her team to some important discoveries.

“Tendons are incredibly important structures, but exceedingly little is known about tendon development. It is very understudied, but it has implications in the treatment of a variety of tendon afflictions, from tendinitis to disorders caused by antibiotics or cancer treatments,” Henry says. “Traditionally, tendons have been thought of as uniform, with the same protein structure throughout. We have found that that is decidedly not the case. Tendon structure is spatially and temporally dynamic. We’re very excited about looking further at how the type and location of tendon proteins change over time.”

Henry and her UMaine colleagues continue to show that the zebrafish model has significant advantages over other research systems. Perhaps best of all, recent studies have shown that many of the processes that occur during zebrafish development are very similar to the developmental changes that occur in mammals, including humans.

“There’s a lot of basic science in this area that we just don’t understand,” says Henry. “We don’t know how these structures grow, how they increase in mass or how the attachment between the tendon and the skeleton is maintained. There’s a real opportunity here to do pioneering work.”

While zebrafish development will remain the primary focus of her research, an opportunity to interact with some of the country’s leading stem cell researchers will soon have Henry working with a slightly larger fish: the dogfish shark. Henry is the recipient of one of a handful of New Investigator Awards from Mount Desert Island Biological Laboratory (MDIBL). The honor will allow Henry to work with MDIBL scientists for several weeks, examining muscle growth and development in the dogfish.

Dogfish developed their unique physiology long before bony fish like the zebrafish evolved. Henry hopes that comparisons between dogfish and zebrafish embryonic development offer insights into the evolution of muscle development and function.

“This award allows my lab to delve into questions that we would be unable to ask without the valuable intellectual and practical resources at MDIBL,” Henry says.

Hoping to make the most effective use of her discoveries, Henry is currently working with UMaine’s administration to develop new opportunities for collaboration with specialists in human genetics and other fields.

“Having a system like this, where we can see the fine details of cell behavior as it forms structures like muscle, facilitates a much more complete understanding of the processes at work. If we’re going to talk about developing treatments for diseases, we need a very thorough understanding of what’s going on,” says Henry.

“Part of what is so exciting about this work is that we are not just using the zebrafish model to recapitulate what has been done in other systems, we’re using the zebrafish to ask questions that aren’t easily answered in other systems to complement what’s known.”

by David Munson

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