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Walk, run, jump, stretch, yawn, chew, reach, grab: Three scientists explore the molecular mechanisms that make it all possible.
May 2011--Popeye rhapsodized about his “lotta muscle.” Arnold Schwarzenegger wouldn’t be Arnold if not for his shirt-popping pecs. Yet, while we marvel at bulging forearms and six-pack abs, muscles still present biologists with many unsolved questions, such as the specific details of how they form and why they atrophy.
At Johns Hopkins, three researchers are examining such questions, using three very different approaches.
Muscles may be the most communal of cells. Unlike most other cell types, skeletal muscle cells, known as myoblasts, fuse together during development, pool the contents of their cytoplasm and form one giant cell (a muscle fiber) containing multiple nuclei. “Myoblast fusion allows hundreds, or even thousands, of individual muscle cells to coordinate their functions as a single unit,” says Elizabeth Chen, assistant professor of Molecular Biology and Genetics. This large, multinucleated unit can then act as a powerful contractile machine.
Chen focuses on the molecular hows and whys of this extraordinary process, using the developing fruit fly embryo as a model system.
Researchers have known that two types of cells are involved in myoblast fusion in the fruit fly: a stationary cell, which remains at a fixed position during the joining of two cells, and a migratory cell, which approaches and adheres to the stationary cell. But the more detailed mechanisms, says Chen, have been “a black box.”
Chen, however, recently elucidated an important piece of the mystery using both light and electron microscopy. Her 20-minute video recording of the process shows an invasive structure protruding from the migratory cell’s membrane as the cell approaches the stationary cell. Electron microscopy studies further revealed finger-like protrusions—which Chen calls podosomes—thrusting into the territory of the stationary cell. “It’s like a little hand reaching out to push on the other cell’s membrane,” says Chen.
As for the migratory cell, it appears to form a ring, or gasket-like seal, around each podosome. The two cell membranes at these regions then blend to form one.
Chen believes that human muscle cells employ a similar mechanism for cell fusion, since most of the molecular components uncovered in flies are also found in human cells.
Although her work focuses on fundamental biology, Chen says her findings might one day help clinicians improve certain types of stem cell therapy designed for treating patients with muscular dystrophy. After they are introduced into a patient, muscle stem cells will need to fuse to form muscle fibers. Understanding the normal mechanism could help clinicians improve cell fusion efficiency in stem cell treatments.
Deactivating a muscle gene, in search of a therapy
In 1997, professor of Molecular Biology and Genetics Se-Jin Lee attracted worldwide attention when he generated a special breed of “mighty mice” by deactivating a gene called myostatin. The lab mice displayed muscles twice as large as normal. Although the finding piqued the interest of many aspiring bodybuilders, Lee says he is not interested in muscular aesthetics but in understanding the basic biology of myostatin gene and protein, and learning how to exploit that knowledge to benefit patients with muscular dystrophy, age-related muscle loss and other muscle diseases.
So for the past 14 years he has focused on understanding how the myostatin protein interacts with other proteins in what appears to be a complex signaling pathway. And he has conducted dozens of experiments aimed at identifying drugs that can inhibit myostatin.
Myostatin is like the body’s bulk police, says Lin; its job is to keep the growth of muscles in check. So, in theory, inhibiting myostatin or other proteins of the myostatin pathway would allow muscles to grow more and perhaps compensate for the muscle loss in diseases such as muscular dystrophy.
“There’s huge pharmaceutical interest in pursuing this strategy,” says Lee. At least five companies have conducted or are conducting clinical trials of myostatin inhibitors.
One of the most promising, according to Lee, is a protein-based therapy developed by Acceleron Pharma. The investigational drug is based on a molecule generated by Lee, which he showed dramatically boosted muscle growth in mice. Now, Acceleron has conducted phase 1 tests of its product in postmenopausal women and demonstrated that the investigational drug increased lean muscle mass throughout the body. The company also began phase 2 trials of the drug in boys with Duchenne muscular dystrophy, but stopped the trial prematurely because some patients developed nosebleeds and other minor bleeding problems. The company plans to address those issues and launch a redesigned study.
“The phase 1 results are pretty exciting,” says Lee. However, he is cautious. The phase 1 study was designed to test the drug’s safety in healthy volunteers, not its therapeutic potential. In muscular dystrophy, muscle fibers are fragile and more susceptible to damage. So building bigger versions of those fibers may or may not compensate for their weakness.
Only a phase 2 study, by Acceleron or another company, will demonstrate whether inhibiting myostatin can improve muscle function in patients with Duchenne muscular dystrophy. Until then, Lee remains hopeful that myostatin inhibitors can offer some therapeutic value, if not as a treatment for muscular dystrophy. Myostatin is central to the regulation of muscle growth, he says. “It’s hard to imagine that a myostatin inhibitor won’t work for some disease.”
Clues from squirrels
From November through April, Ronni Cohn keeps something unusual in his laboratory’s refrigerators: hibernating ground squirrels. The fridge’s cool temperatures prompt the animals to enter their natural cycle of hibernation.
In the spring, as the squirrels arise from their winter slumber, Cohn studies their muscle biology.
The animals are helping to elucidate the molecular mechanisms that underlie muscle atrophy, says Cohn, an assistant professor of pediatrics, neurology, and the McKusick-Nathans Institute of Genetic Medicine. Muscles shrink and weaken if they are not exercised. Muscle loss also occurs in certain diseases, and it is an inevitable consequence of aging. Age-related muscle loss, or sarcopenia, affects 40 percent of people who are age 80 or older. Such debilities increase the risk of falls and pose a significant public health problem, one whose costs came to $18.5 billion in 2000, according to one analysis.
Ground squirrels, however, appear to defy the rule that says muscles diminish if not used. “For six months, they don’t move, eat or drink,” says Cohn. “And then they wake up and walk and jump around like nothing ever happened.”
In his measurements of various muscle-associated genes and proteins in squirrels coming out of hibernation, Cohn finds that the molecular profiles of the animals are similar to those seen in endurance athletes, such as marathon runners, and in athletes whose sport requires strength, such as weightlifters. “It’s turning out to be an incredibly fine-tuned system of many pathways,” he says.
Further illuminating those pathways could help scientists find ways to mimic their features in patients seeking treatments for muscle loss.
Such research will only become more vital as the population ages, adds Cohn, and more of us see our once-taut physiques diminish. The Popeyes and Arnolds of the world won’t remain buff forever. Perhaps medicine will one day offer them and all of us new strategies for keeping muscles healthy and strong even as we age.
*Ronni Cohn left Johns Hopkins University late 2012.
Se-Jin Lee on myostatin and muscle growth