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Lithium boosts muscle strength in mice with rare muscular dystrophy

New drug target identified

by Tamara BhandariApril 18, 2019

Andrew Findlay

Standing up from a chair, climbing stairs, brushing one’s hair – all can be a struggle for people with a rare form of muscular dystrophy that causes progressive weakness in the shoulders and hips. Over time, many such people lose the ability to walk or to lift their arms above their heads.

This form of the disease – called limb girdle muscular dystrophy – affects a few thousand people nationwide. Like other rare illnesses, it tends not to attract much attention from researchers and funding agencies, so progress toward developing therapies has been slow. But a team at Washington University School of Medicine in St. Louis that identified a subtype of the disease in 2012 has shown that lithium improves muscle size and strength in mice with this form of muscular dystrophy. The findings, published April 18 in Neurology Genetics, could lead to a drug for the disabling condition.


“There are no medications available for people with limb girdle muscular dystrophy, so we are very excited to have a good therapeutic target and a potential therapy,” said senior author C. Chris Weihl, MD, PhD, a professor of neurology who treats people with muscular dystrophy at the university’s Neuromuscular Disease Center. “This has been an amazing project. It all began when we diagnosed a patient with muscular dystrophy of unknown cause. Genetic sequencing then helped us identify a new subtype, and we’ve been able to take that all the way through to a possible therapy.”

Limb girdle muscular dystrophy can be caused by variations in any one of more than a dozen different genes. Several years ago, Weihl and colleagues – including neurologists Robert Baloh, MD, PhD, and Matthew Harms, MD – identified two families in which several members had symptoms of the condition but none of the known genetic variants. By analyzing the DNA of affected and unaffected members of both families, the researchers found that a variation in the gene DNAJB6was responsible for their muscle weakness.

While the researchers had found the faulty gene, it wasn’t immediately clear why an alteration to that gene caused people’s muscles to atrophy. To find out, Weihl and co-first authors Andrew Findlay, MD, a clinical fellow in neurology, and Rocio Bengoechea Ibaceta, PhD, a staff scientist, cut the gene out entirely, expecting to see even more muscle loss when the gene was absent.

They found the opposite: Without DNAJB6, muscle fibers grew to three times their normal size.

“When Drew showed me these enormous muscle fibers, I just didn’t understand it,” Weihl said. “But Drew pointed out that we were on the right pathway, but perhaps going the wrong direction. Something in this pathway is important for muscle growth.”

The researchers tried again, this time using genetically modified mice that Weihl and colleagues had engineered in 2015. These mice carried the same genetic variant as the patients, and like the patients, they developed progressive muscle weakness in adulthood. Using muscle from these mice, the researchers discovered that disease variants overactivate a protein that suppresses muscle growth. Moreover, inhibiting the protein – called GSK3beta – with lithium chloride improves mice’s strength and muscle mass.

“Before treatment, mutant mice had roughly one-fifth the strength of the normal mice,” Findlay said. “After a month of treatment, they improved to 75 percent of the normal mice. It’s a big jump.”

Lithium chloride was once sold as table salt but was taken off the shelves in 1949, when doctors realized that sprinkling it liberally on food can be deadly. But other forms of lithium such as lithium carbonate and lithium citrate are used to treat some psychiatric illnesses, so it’s possible a safe form of lithium can be found to treat the rare muscular dystrophy.

“I don’t want people to go out and take lithium chloride right now,” Findlay said. “We’ve shown that this protein is a promising therapeutic target, but more work needs to be done.”

Before any compound targeting the protein is tested in humans, a better understanding of limb girdle muscular dystrophy is needed. The disease is so rare that doctors have not defined how quickly different people lose strength and how the course of the disease differs in people whose condition is caused by variations in different genes.

“We’re at a point where therapeutic development has outpaced our understanding of the natural history of this disease,” Weihl said. “We have a therapeutic target, but we don’t fully understand how patients progress when they’re not treated. We need to understand as many people with this rare disease as possible so when we do start testing an investigational drug, we can be confident that it is changing the course of the disease.”

Weihl, Findlay, and colleagues around the U.S. and U.K. are planning a study of people with limb girdle muscular dystrophy caused by variations in any gene. The study will map disease progression in such people in preparation for upcoming treatment trials. Participants will make annual visits to the neuromuscular clinic to undergo functional assessments such as timed stair climbs and fill out questionnaires rating their ability to perform tasks of daily life.

Findlay AR, Bengoechea R, Pittman SK, Chou TF, True HL, Weihl CC. Lithium chloride corrects weakness and myopathology in a preclinical model of LGMD1D. Neurology Genetics. April 18, 2019. DOI: 10.1212/NXG.0000000000000318

This study was supported by the National Institutes of Health (NIH), grant numbers AG031867, AG042095, and AR068797; and the Muscular Dystrophy Association.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Tamara covers infectious diseases, molecular microbiology, neurology, neuroscience, surgery, the Institute for Informatics, the Division of Physician-Scientists and the MSTP program. She holds a double bachelor's degree in molecular biophysics & biochemistry and in sociology from Yale University, a master's in public health from the University of California, Berkeley, and a PhD in biomedical science from the University of California, San Diego. She joined WashU Medicine Marketing & Communications in 2016. She has received three Robert G. Fenley writing awards from the American Association of Medical Colleges: a bronze in 2020 for "Mind’s quality control center found in long-ignored brain area," a silver in 2022 for "Mice with hallucination-like behaviors reveal insight into psychotic illness," and a bronze in 2023 for "Race of people given Alzheimer’s blood tests may affect interpretation of results." Since January of 2024, Tamara has been writing under the name Tamara Schneider.