Body’s Response to Disease’s Basic Gene Defect Leads to Buildup of Mis-Produced Fat Cells That Causes Abrupt Decline in Muscle Function and Is Key to Sudden Onset of Symptoms in Limb-Girdle Muscular Dystrophy Type 2 (LGMD2B) in Young Adulthood

Research led by faculty at Children's National in Washington, DC, and published online on June 3, 2019 in Nature Communications, shows that the sudden appearance of symptoms in limb-girdle muscular dystrophy type 2B (LGMD2B) is a result of impaired communication between different cell types that facilitate repair in healthy muscle. The open-access article is titled “Fibroadipogenic Progenitors Are Responsible for Muscle Loss in Limb Girdle Muscular Dystrophy 2B.” Of particular interest are the fibro/adipogenic precursors (FAPs), cells that typically play a helpful role in regenerating muscle after injury by removing debris and enhancing the fusion of muscle cells into new myofibers. LGMD2B is caused by mutations in the DYSF gene that impair the function of dysferlin, a protein essential for repairing injured muscle fibers. Symptoms, like difficulty climbing or running, do not appear in patients until young adulthood. This late onset has long puzzled researchers, as the cellular consequences of dysferlin's absence are present from birth and continue through development, but do not impact patients until later in life. The study found that in the absence of dysferlin, muscle gradually increases the expression of the protein annexin A2 which, like dysferlin, facilitates repair of injured muscle fiber. However, increasing annexin A2 accumulates outside the muscle fiber and drives an increase in FAPs within the muscle and also influences these FAPs to differentiate into adipocytes, forming fatty deposits. Shutting down annexin A2 or blocking the adipocyte fate of FAPs using an off-the-shelf medicine arrests the fatty replacement of dysferlinopathic muscle.
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