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Studies by researchers in the United States and Spain have found that the relatively late-onset symptoms of a genetic muscle disorder known as limb-girdle muscular dystrophy type 2 (LGMD2B) occur as a result of communication problems between cell types involved in repairing muscle. Results from research in mice and tests on human tissue indicated that this impaired communication directs a type of cell known as fibro/adipogenic precursors (FAPs) to differentiate into fat cells that, over time, form fatty deposits instead of new muscle.

“We propose a feed-forward loop in which repeated myofiber injury triggers chronic inflammation which, over time, creates an environment that promotes FAPs to accumulate and differentiate into fat,” commented Jyoti K. Jaiswal, PhD, principal investigator at the Center for Genetic Medicine Research at Children’s National Health System. “This, in turn, contributes to more myofiber damage.” Jaiswal is senior author on the team’s paper, published today in Nature Communications, and titled, “Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B.”

LGMD2B is one of a group of muscle diseases that are caused by mutations in the gene for dysferlin, a protein that is essential for repairing injured muscle fibers. Lack of dysferlin compromises myofiber repair and causes chronic muscle inflammation. What isn’t clear is why, given that dysferlin is missing from birth in affected individuals, typical symptoms tend not to appear until early adulthood. “… deficits do not explain the late and abrupt disease onset, progressive nature, or specific muscle involvement seen in patients or in mouse models,” the authors commented.

Recent studies have discovered fat deposits in the muscle tissues of symptomatic dysferlinopathic patients and in mouse models. Strength exercises have also been found to exacerbate the phenomenon in patients, “suggesting a link between myofiber injury and adipogenic replacement of LGMD2B muscle,” the scientists wrote. The team’s previous work had implicated a protein known as annexin A2 (AnxA2) in the link between injury and fat deposits in dysferlin-deficient myofibers. Building on this finding, the researchers further studied the effects of dysferlin loss on FAP cells in muscle tissue.

Their results, in dysferlinopathic patients and in mouse models, found that in the absence of dysferlin, muscle gradually increased expression of AnxA2, a protein that is also involved in repairing injured muscle fibers. But in the context of dysferlinopathy AnxA2 accumulated over time outside the muscle fibers, and triggered increased numbers of FAPs within the muscle, and their differentiation into adipocytes. The team’s experiments showed that exposing purified dysferlinopathic FAPs to AnxA2 resulted in a doubling in spontaneous adipogenic FAP differentiation. Collective data provided “direct evidence supporting that extracellular AnxA2 is not only necessary, but also sufficient for driving FAP-mediated in vivo adipogenic conversion of the regenerating dysferlinopathic muscles.”

The scientists also showed that either blocking AnxA2, or chemically inhibiting adipogenic FAP differentiation using the small molecule anticancer matrix metalloproteinase (MMP) inhibitor batimastat effectively halted adipogenic muscle loss. Batimastat therapy was shown to reduce FAP adipogenesis in vitro, as well as hold back injury-triggered lipid formation in vivo. Batimastat also increased muscle function in the experimental models.

Working with colleagues at the Hospital de la Santa Creu in Barcelona, the team examined muscle biopsies from LGMD2B patients who had mild to severe symptoms. They found that adipogenic deposits originated in the extracellular matrix space between the muscle fibers, and that the degree of accumulation correlated with increased disease severity. There was a similar link between increased lipid accumulation between myofibers and disease severity in dysferlin-deficient animal models. The process could be accelerated by muscle injury, triggering increased adipogenic replacement in areas that would in healthy tissue be occupied by muscle cells. “Adipogenic accumulation becomes the nucleating event that results in an abrupt decline in muscle function in patients,” stated lead study author Marshall Hogarth, PhD.

The findings point to new approaches for treating relevant dysferlinopathies, Jaiswal noted. “Accumulation and adipogenic differentiation of FAPs is responsible for the decline in function for dysferlinopathic muscle. Reversing this could provide a therapy for LGMD2B, a devastating disease with no effective treatment.”

“Here, we provide evidence that disease onset and progression in dysferlinopathy is not driven solely by the myofiber and inflammatory cell-specific defects, but by creation of an extracellular niche resulting in proliferation and adipogenic differentiation of muscle-resident FAPs,” the authors concluded “… while dysferlinopathy is driven by a myofiber specific deficit, it is the impaired cellular interactions between myofibers, inflammatory cells, and FAPs that is causative for disease initiation and severity. This view of the disease opens up previously unrecognized avenues to intervene.”

Potential therapeutic strategies could potentially include the use of MMP inhibitors such as batimastat, but also other drugs such as promethazine, which also inhibit FAP adipogenesis, the authors stated. “Irrespective of the precise therapeutic approach that would be efficacious, our study identifies the accumulation and adipogenic differentiation of FAPs as a central target to prevent the precipitation of cellular deficits into the abrupt onset of disease in dysferlinopathies. Moreover, such therapies would be complementary to the ongoing efforts to restore dysferlin expression in terminally differentiated myofibers.”

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