Scavenger cell removes the repair patch. Scale bar: 4 µm. [Volker Middel / KIT]
Scavenger cell removes the repair patch. Scale bar: 4 µm. [Volker Middel / KIT]

Putting in that extra effort on the elliptical will register pretty quickly, as the burning sensation in your legs begins to radiate outward—a feeling often caused by microruptures in the cell membrane of muscle fibers. For muscle cells to survive, the holes in the cell membrane must be sealed swiftly; yet the particular mechanism behind the closures has remained somewhat of a mystery.

Now, investigators at the Karlsruhe Institute of Technology (KIT) in Germany have been able to observe this cell repair process through the use of high-resolution, real-time microscopy. The researchers found that it only takes a few seconds until proteins from the inside of the injured cell form a repair patch that finally closes the hole in the membrane. Moreover, the research team observed that scavenger cells moving around within the muscle virtually perform nanosurgery to remove this repair patch later and restore the normal cell membrane structure.  

Skeletal muscles cells have effective mechanisms for the repair of ruptures in their cell membranes. These fractures are due to mechanical stress to which we expose our muscles, even when doing healthy exercises. The cell membrane is a crucial barrier that is essential to the proper functioning and survival of cells, and if this wall collapses and cannot be repaired quickly, the muscle cell will die, resulting in a loss of muscle mass. If repair proteins such as dysferlin do not work properly, then muscles begin to atrophy—leading to severe disabilities and premature death.

In the current study, the KIT researchers developed new techniques to observe membrane repair processes with ultra-high resolution in real time in human cells and in muscle cells of zebrafish embryos. The investigators provided evidence that the repair patch was assembling itself from repair proteins, such as dysferlin or annexins, and also accumulated the lipid phosphatidylserine (PS).

The authors wrote that they examined “sarcolemmal repair in live zebrafish embryos by real-time imaging. Macrophages remove the patch. PS, an ‘eat-me’ signal for macrophages, is rapidly sorted from adjacent sarcolemma to the repair patch in a Dysferlin (Dysf) dependent process in zebrafish and human cells. A previously unrecognized arginine-rich motif in Dysf is crucial for PS accumulation. It carries mutations in patients presenting with limb-girdle muscular dystrophy 2B. This underscores the relevance of this sequence and uncovers a novel pathophysiological mechanism underlying this class of myopathies.”

The findings from this study were published recently in Nature Communications in an article entitled “Dysferlin-Mediated Phosphatidylserine Sorting Engages Macrophages in Sarcolemma Repair.”

The KIT scientists provided video evidence showing how macrophages latch on to and consume the repair patch. Once the patch has been completely removed, the cell envelope is fully restored. Thus, the repair of the membrane in muscle fibers requires, in addition to the formation of repair patches in the injured cell, the aid of macrophages roaming within the muscle. Furthermore, the researchers demonstrated that a short amino acid sequence in the dysferlin repair protein is responsible for the phosphatidylserine transport.

“Our data show that membrane repair is a multi-tiered process involving immediate, cell-intrinsic mechanisms as well as myofiber/macrophage interactions,” the authors concluded. The authors are optimistic that their new findings may contribute to the development of therapies against muscle-wasting diseases.

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