University of Iowa researchers, working in a mouse model of muscular dystrophy (MD), have established new molecular signatures associated with membrane protein complexes that typify the disease, possibly opening the way to new and suitable therapies, according to the study, “Molecular signatures of membrane protein complexes underlying muscular dystrophy,” published in Molecular & Cellular Proteomics journal.
Muscular dystrophies are characterized by a gradual degeneration and weakness of skeletal muscle. There are nine prominent forms of MD affecting different body muscles, but most are caused by a lack of proteins associated with the cell membrane in skeletal muscle called sarcolemma, leading to muscular instability and cell death. This protein deficiency, in turn, is linked to mutations in the genes encoding for the sarcolemmal dystrophin-glycoprotein complex (DGC) units.
An understanding of the pathological mechanisms involved in DGC is expected to provide new disease insights and to facilitate the development of therapies. However, studying the molecular composition of DGC is challenging due to a lack of the appropriate biochemical approaches.
Researchers proposed an analytical method that uses protein correlation profiling to model the molecular composition of DGC in mouse skeletal muscle tissue, either without or with DGC mutations (mutant mice). When the team examined bioinformatic data of mutant mice, they found that the cell adhesion processes that allow cells to stick together are controlled by a protein complex found in DGC. This complex species is called NFκB and is responsible for several functions, such as the transcription of DNA, production of cell signaling molecules, and cell survival. The data also helped confirm previous findings that NFκB-regulated pathways govern the pathophysiology of DGC-related MD.
These results also revealed that the skeletal muscle of DGC mutant mice is characterized by activated inflammatory and compensatory mechanisms. “It remains to be determined whether our biochemical workflow is suitable for to the study of other well-characterized membrane protein complexes in mammalian systems,” the authors wrote.
“The molecular interrogation of the DGC in skeletal muscle tissue will facilitate the identification of novel components of the DGC, provide deeper molecular insights into how drugs influence the biochemical composition of the DGC, and uncover active compensatory pathways and/or mechanisms at the molecular and cellular level to influence the skeletal muscle phenotype in muscle dystrophies,” they concluded.