Rapamycin administered to a mouse model of dystroglycanopathy, a particular form of muscular dystrophy, worked to reduce fibrosis and inflammation, researchers reported, while enhancing muscle strength.
The study, “Four-week rapamycin treatment improves muscular dystrophy in a fukutin-deficient mouse model of dystroglycanopathy,” was published in the journal Skeletal Muscle.
Eystrophin-glycoprotein complex (DGC), a protein complex, is crucial for membrane stability on our cells. The protein called alpha-Dystroglycan (alpha-DG) is an important member of this complex. However, to work properly, the protein requires a modification to its structure that is mediated by O-mannose glycosylation.
Disrupting this process impairs alpha-DG function, resulting in a group of diseases known collectively as secondary dystroglycanopathies, which are a subset of muscular dystrophy disease. These diseases are characterized by progressive muscle pathology along with variable involvement of the brain and eyes.
Until now, researchers detected mutations in at least 15 genes that culminate in the disruption of alpha-DG glycosylation. One such gene is called Fukutin (FKTN).
Researchers investigated the mechanism underlying loss of function of FKTN and how it might relate to dystroglycanopathy. Previous studies, analyzing muscles from dystroglycanopathy patients and animal models of the disease, found muscle fiber sizes varied considerably, with tissues presenting both large (hypertrophic) and diminished (atrophic) cells. These findings suggest that pathways controlling cell growth could be deregulated and contribute to the disease.
A protein called TOR is a key regulator of pathways controlling cell growth. So, the researchers analyzed the expression of TOR protein in the muscle of Fktn knockout mice (i.e., mice whose Fukutin gene has been deleted). They observed that the muscles from these mice had TOR signaling activated — but this signaling only occurred after the disease began. This means that TOR signaling pathway abnormalities are not the cause of dystroglycanopathy.
They hypothesized, however, that targeting TOR could be of potential therapeutic benefit to these mice. They treated Fktn knockout mice with rapamycin, a known inhibitor of TOR protein (in fact, TOR is an acronym for target of rapamycin). The drug was administered daily for four weeks.
Researchers observed that rapamycin treatment reduced fibrosis, inflammation, and activity-induced damage. It increased muscle fiber size in Fktn knockout mice when compared to non-treated controls. Moreover, the treatment led to significantly higher muscle torque (i.e., the force applied by the muscles through a moment arm of a given length) at the end of the treatment.
These results suggest that signaling mediated by TOR protein is deregulated in dystrophic dystroglycanopathy skeletal muscle, and therapeutic targeting of TOR-mediated pathways may reduce disease burden in dystrophic patients.
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