Biomedical engineers at Duke University have created a new method to study and test treatments for rare muscle diseases called dysferlinopathy or LGMD2B. They grow complex, functional 3D muscle tissue from stem cells in the lab, mimicking patient symptoms and treatment responses.
Their first study uncovered the biological mechanisms behind LGMD2B’s mobility loss. They showed that combining existing treatments might relieve some of the worst symptoms.
LGMD2B affects about eight people per million worldwide. Unlike the more common Duchenne muscular dystrophy, LGMD2B affects both men and women, appears later in life (late teens or early 20s), and is rarely fatal. However, patients experience severe weakness in the legs and shoulders, often requiring wheelchairs for life.
LGMD2B is caused by a genetic disorder that prevents the body from producing functional dysferlin protein, which is crucial for muscle function. There are no approved treatments or cures. Dysferlin has many roles, including repairing muscle membranes, regulating calcium for muscle contraction, and controlling metabolism. Affected muscles accumulate fat before degenerating and being replaced by fat cells, a rare phenomenon even among muscular dystrophies.
Research is challenging because mouse models show mild symptoms, making studies slow and complicated. Mice can still walk and don’t show symptoms until nearly halfway through their lifespan. Additionally, dysferlin is found in other cell types, and metabolic changes in mice and patients complicate understanding the disease.
Bursac and his colleague Alastair Khodabukus used an engineered muscle platform they developed for nearly a decade to overcome these challenges. The Bursac Lab was the first to grow contracting, functional human skeletal muscle in a Petri dish, and they have refined this process to study muscle strength, metabolism, and repair. This system allowed them to focus on the effects of dysferlin on skeletal muscle without interference from other cell types or altered blood metabolite profiles.
Their study used induced pluripotent stem cells (IPSCs) from LGMD patients provided by The Jain Foundation. They matured these stem cells into muscle fibers and tested them over six weeks. The lab-grown muscles displayed issues similar to those found in patients. The model replicated many clinical aspects of the disease in a Petri dish, which has provided new insights into LGMD2B’s muscle-specific aspects.
The researchers found that muscle strength loss was due to issues with calcium handling, not muscle structure or size. Muscle contractions occur when calcium is released in muscle cells. However, in diseased cells, calcium leaks reduce the amount available for contractions, resulting in weaker muscles.
They also discovered that the lack of dysferlin prevented muscle cell repair and contributed to fat accumulation in muscle fibers. This was partly due to an inability to burn fatty acids for energy, which has puzzled the medical community.
The researchers tested two drugs identified through mouse models but have yet to test them on humans. Dantrolene aims to stop calcium leaks from muscle cells, and nandrolone, recently approved for Duchenne muscular dystrophy, also showed potential.
Together, the drugs prevented calcium leaks, helped repair cell membranes, and restored muscle strength. They also reduced muscle fat accumulation but didn’t entirely prevent or improve fat burning.
The team plans to add immune and fat cells to their experiments for more complexity and to understand metabolism disruptions better. They also aim to find new drugs that restore muscle strength and repair.
Alastair Khodabukus, a Research Scientist at Duke University, said,“Currently, we have a basic muscle-only system. We need to study the interaction between immune, fat, and muscle cells to understand what drives muscle loss and fat replacement in patients,”
Journal reference:
Alastair Khodabukus, Neel K. Prabhuetal., Bioengineered Model of Human LGMD2B Skeletal Muscle Reveals Roles of Intracellular Calcium Overload in Contractile and Metabolic Dysfunction in Dysferlinopathy. Advanced Science. DOI: 10.1002/advs.202400188.
>>> Read full article>>>
Copyright for syndicated content belongs to the linked Source : Tech Explorist – https://www.techexplorist.com/rare-muscle-diseases-created-lab-grown-muscles/85429/#utm_source=rss&utm_medium=rss&utm_campaign=rare-muscle-diseases-created-lab-grown-muscles
