Losing muscle to fat: the misdirected fate of a multipotent stem cell grows LGMD2B

A research conducted by teachers of the Children's National published online June 3, 2019, in Nature Communications shows that the sudden onset of symptoms in limb muscular dystrophy 2 (LGMD2B) is due to impaired communication between different types of cells facilitating the repair of a healthy muscle. Fibro / adipogenic precursors (FAPs) are particularly interesting, cells that generally play a useful role in muscle regeneration after injury by removing debris and enhancing fusion of muscle cells into new myofibers.

LGMD2B is caused by mutations in the DYSF gene that alter the function of dysferlin, a protein essential for the repair of damaged muscle fibers. Symptoms, such as difficulty climbing or running, do not occur in patients before the onset of adulthood. This late onset has long left researchers puzzled, as the cellular consequences of the absence of dysferlin are present from birth and continue throughout development, but only affect patients later in life .

The study revealed that in the absence of dysferlin, the muscle gradually increases the expression of the protein annexin A2 which, like dysferlin, facilitates the repair of the injured muscle fiber. However, the increase of annexin A2 accumulates on the outside of the muscle fiber and causes an increase in the number of FAP in the muscle and also encourages them to differentiate into adipocytes, forming fatty deposits. The closure of annexin A2 or the blockage of FAP by adipocytes with the help of a standard drug stops the fatty replacement of the dysferlinopathic muscle.

"We propose a feed-forward loop in which repeated lesions due to a myofibre trigger chronic inflammation that, over time, creates an environment that favors the accumulation and differentiation of FAP into fat. increase the damage caused by the myofibre, "says Jyoti K. Jaiswal, MSc, Ph.D., senior researcher at the National Children's Research Center for Genetic Medicine and lead author of the study.

"The adipogenic accumulation becomes the nucleating event that results in an abrupt decline in muscle function in patients.This new vision of LGMD2B disease opens up new avenues for intervention," adds Marshall Hogarth, Ph.D. , lead author of the study.

A research team led by Jaiswal collaborated with Eduard Gallardo and Jordi Diaz Manera of the Santa Creu Hospital in Barcelona, ​​Spain, to examine muscle biopsies of people with mild to severe LGMD2B symptoms. They discovered that adipogenic deposits originate in the extracellular matrix space between muscle fibers, the degree of accumulation being related to the severity of the disease. They found a similar progressive increase in lipid accumulation between myofibers, which predicts the severity of the disease in dysferlin-deficient experimental models. In addition, this process can be accelerated by muscle injury, resulting in an increase in adipogenic replacement in areas otherwise occupied by muscle cells.

"The accumulation and adipogenic differentiation of PAFs are responsible for the decline of dysferlinopathic muscle function.Inverting this trend could provide therapy for LGMD2B, a devastating disease without effective treatment," predicts Jaiswal as the team continues its research in this area.

Batimastat, an anti-cancer drug that inhibits extracellular matrix metalloproteinase, is a promising drug. This drug reduces the adipogenesis of APF in vitro and decreases lipid formation triggered by injury in vivo. In experimental models, batimastat also increases muscle function.

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Besides Jaiswal, Hogarth, Gallardo and Diaz Manera, other co-authors of the study include Aurelia Defour, Christopher Lazarski, Terence A. Partridge and Kanneboyina Nagaraju, all of whom belong to Children's National.

The financial support for the research described in this article was provided by the Muscle Dystrophy Association under the awards MDA477331 and MDA277389, by the National Institute of Arthritis and Musculoskeletal Diseases and Skin Rewarded by the awards R01AR055686 and P50HDAR08.