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Muscle Cell Death Infuses New Life in Muscles!
The title of this article might have been dilemmic, but it's true! Death of muscle cells infuses life in muscles! In a recent research publication of Amelia E. Hochreiter-Hufford et al., in The Nature, published on 24 April 2013, role of Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion was described. Let me brief the jest of this research, first by throwing some light on the terms used above:

Myoblast Fusion:
The birth of skeletal muscles takes place when precursor-myoblast cells fuse together to form multinucleated myofibres. So, the term myoblast fusion indicates the birth of muscles.
Following is a very short view of how human myoblasts fuse together:

Apoptotic cells
Most of you must be familiar with the term," Apoptosis". Apoptosis refers to programmed cell death. And, so apoptotic cells are those at the verge of death (death programmed in the genome).

Phosphatidylserine receptor BAI1
BAI1 is a membrane protein (a GPCR in nature, the 7 -pass protein family) of the phagocytes which is well known for mediating the recognition of phosphatidylserine (chemically 1,2-diacyl-sn-glycero-3-phospho-L-serine, a phospholipid) on apoptotic cells.
So, till date, it was only known that during phagocytosis, the BAI1 GPCR recognized the universal marker of phosphatidylserine on apoptotic muscle cells, completing the cell death, untill recently, when Amelia E. Hochreiter-Hufford and team from University of Virginia, established the fact that "without apoptotic cells, new cells can't be born!"

Simple Experiments Which Proved The Same:

Growth Experiment:
C2C12 myoblasts (a mouse myoblast cell line), exhibit no growth/fusion in fully supplemented growth medium. But when apoptotic myoblasts are added to this culture, the fusion starts taking place to give birth to new muscle cells!!
zVAD Experiment:
zVAD is a caspase inhibitor, which inhibits apoptosis. Whereas fusion was inhibited in zVAD treated cultures. Collection of floating cells (apoptotic cells) from non-zVAD treated cultures to the zVAD treated culture activated myoblast fusion/birth of muscles!
Phosphatidylserine Masking:
As, mentioned earlier, phosphatidylserine is the universal marker of apoptotic cells. When, it's masked using GST-TSR protein, myoblast fusion cannot take place. Again establishing the significance of recognition of the presence of apoptotic cells in the vicinity of growing myoblast culture.
BAI1 Overexpression:
Increase in the expression of BAI1 protein increased the rate of fusion, again establishing the close link between the apoptotic cells and new cells.
Casp3−/− Mice Test:
It was observed that Casp3−/− mice (those lacking caspase 3: an apoptosis protein) have stunted growth when compared to the control set of mice. Their skeletal muscle growth was much lesser than the control set.

Briefing the Concept:
When myoblast fusion is about to take place, a fraction of the cells follow the apoptotic path of expressing phosphatidylserine on their surface, which is recognized by the BAI1 protein on the phagocytes. The triggering of expression of BAI1 protein in turn catalyzes the myoblast fusion process by activating ELMO/Dock180/Rac1 pathway (an indispensable pathway for cytoskeleton arrangement and fusion of myoblasts). Mingjian Lu & Kodi S. Ravichandran's publication on "Dock180–ELMO Cooperation in Rac Activation" gives a brilliant detail of this pathway. Blocking the apoptosis tends to impair the fusion, while catalyzing the same tends to do the favor to fusion. In Human myoblasts also, it has been found that myotubes synthesis is triggered upon addition of apoptotic cells. It must be kept in mind that it's not the apoptotic cells which take part in fusion. Once a fraction of cells is differentiated towards apoptosis, it will progress to death ultimately, but it tends to trigger the fusion among the healthy myoblasts through contact-mediated signalling with the neighboring cells. Even an injured muscle tissue won't get repaired if the apoptotic pathway of the cells is blocked/inhibited. The same was observed in cas-/- and bai1-/- mice, which exhibited no repair of injured tissue as compared to the control set of mice. Thus establishing the fact that "Without Apoptosis of Muscle Cells, One Cannot Imagine The Birth of New Muscles!"

These findings set a capstone in the field of muscle growth/regeneration/degeneration studies. The recognized role of apoptotic cells in muscular development can change the approach towards treatment of myo-degenerative diseases like muscular dystrophy/paralysis etc. Also, ex-situ culturing of muscle cells will be very easy now having realized the catalyzing power of overexpressed BAI1 protein/phosphatidylserine. Considered altogether, the research is exceptional and highly productive in terms of it's utility for the field of medicine.

References/Suggested Readings:

Amelia E. Hochreiter-Hufford, Chang Sup Lee, Jason M. Kinchen, Jennifer D. Sokolowski, Sanja Arandjelovic, Jarrod A. Call, Alexander L. Klibanov, Zhen Yan, James W. Mandell & Kodi S. Ravichandran. Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion: Nature 497, 263–267 (09 May 2013)

Park, D. et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430–434 (2007)

Mingjian Lu, Kodi S Ravichandran. Dock180-ELMO cooperation in Rac activation:Methods in Enzymology:406:388-402 (2006)
Sunil Nagpal
MS(Research) Scholar, IIT Delhi (Alumnus)
Advisor for the Biotech Students portal (
Computational Researcher in BioSciences at a leading MNC

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