Spinal muscle changes may offer an early clue in dysferlinopathy - Children's National

Changes in the muscles that support the spine may begin long before muscle loss shows up in the legs, opening a potentially earlier window to catch and track dysferlinopathy. In a new EMBO Molecular Medicine study, researchers at Children's National used advanced magnetic resonance imaging (MRI) to identify this early muscle loss - where damaged muscle gets replaced by fat) - and linked it directly to changes in walking. The discovery could transform how doctors track this rare form of muscular dystrophy and reveal a promising new drug target to slow disease progression.

The hold-up in the field

Dysferlinopathy causes progressive muscle weakness that alters how patients stand and walk, eventually leaving many reliant on a wheelchair. Yet researchers have not fully understood what triggers the disease or drives its worsening over time, leaving patients without any approved treatment options. In particular, loss of the core muscles along the spine and how they contribute to walking difficulties along with the underlying cellular changes that drive this damage have never been directly studied.

Moving the field forward

The study revealed that fat buildup in specific back muscles occur during the very early stages of dysferlinopathy. In research models, MRI scans caught fat replacing back muscle well before damage was visible in the thigh muscles, and these core muscle changes directly impaired walking balance and stride.

The research team also pinpointed the biological culprit: a specific group of muscle-repair stem cells called fibroadipogenic progenitors (FAPs). In dysferlinopathy, a chemical signaling pathway (Wnt/β-catenin) inside these cells breaks down, causing them to turn into fat tissue instead of helping repair the muscle. When the researchers used an experimental drug (a GSK3 inhibitor) to restore this chemical pathway, it prevented fat buildup in both spinal muscles and injured leg muscles.

The patient impact

The findings suggest that back muscle MRI scans could become a powerful new diagnostic tool to catch dysferlinopathy earlier and track its progression more accurately. Additionally, identifying GSK3 as a therapeutic target opens the door to developing drugs that actively prevent muscle loss.

While further research and clinical testing are required before these approaches reach patient care, uncovering this early physical marker and a targeted drug strategy to address it creates exciting new avenues for earlier diagnosis and targeted treatment.

"Identifying an early anatomical feature of this disease and drugs that therapeutically target it opens avenues for earlier diagnosis and development of treatments," said Jyoti K. Jaiswal, MSc, PhD, principal investigator for the Center for Precision Medicine and Genomics Research at the Children's National Research Institute and the study's senior author.

Children's National leads the way

Children's National brings over two decades of expertise in uncovering the biological mechanisms behind dysferlinopathy and pioneering potential treatments, including gene therapies designed to restore the missing dysferlin protein. Demonstrating the power of patient-centered science, this study included a patient's family member as an active researcher and author, bringing crucial real-world perspective to the laboratory team.

This research was supported by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Jain Foundation.

Additional Children's National authors for the study include Young Jae Moon, MD, PhD; Nikki McCormack, PhD; Thomas Diehn, BS; Surajit Bhattacharya, PhD; Daniel C. Bittel, DPT, PhD; and Marshall Hogarth, PhD.