Newly published research identifies key mechanisms of skeletal muscle regeneration and growth of muscles following resistance exercise. It’s a finding that opens the door to the development of targeted therapies for various muscle disorders, like Muscular Dystrophy, which affect millions of people worldwide. 

When it comes to muscles and muscle disorders, the importance of a discovery like this cannot be overstated.  
 
Skeletal muscles are formed during embryonic development by the fusion of hundreds of specialized cells called myoblasts. Adult skeletal muscles maintain regenerative capacity, which is attributed to the presence of muscle stem cells, named satellite cells.  

After injury, satellite cells undergo several rounds of proliferation followed by their differentiation into myoblasts. These myoblasts once again fuse with each other and to injured myofibers to accomplish muscle regeneration.  

In many muscular disorders, this intrinsic capacity of muscles to regenerate is diminished resulting in the loss of muscle mass and function. 

The researchers found that Inositol-requiring enzyme 1, a key signaling protein, is essential for myoblast fusion during muscle formation and growth. 

“During muscle regeneration, IRE1 augments the activity of X-box binding protein 1 which in turn stimulates the gene expression of multiple transmembrane proteins required for myoblast fusion,” reports the senior author, in EMBO Reports. 

According to researchers, increasing the levels of IRE1 or XBP1 in muscle stem cells outside the body, followed by their injection in patients’ muscle tissues will improve muscle repair and reduce the severity of disease.    

“We also found that augmenting the levels of IRE1α or XBP1 in myoblasts leads to the formation of myotubes (muscle cells) having an increased diameter,” said the senior author. 

Transcriptome analysis revealed that knockdown of IRE1α or XBP1 dysregulates the gene expression of molecules involved in myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of multiple profusion molecules, including myomaker (Mymk).

Spliced XBP1 (sXBP1) transcription factor binds to the promoter of Mymk gene during myogenesis. Overexpression of myomaker in IRE1α-knockdown cultures rescues fusion defects.

“Size is very important for muscle. Muscle grows only in size, not in number,” said the first author on the article. “Muscular people have larger muscle cells. Larger muscles generally work better- can lift more weight, run and walk faster, and improve overall metabolism of the body and prevent various diseases, such as type II diabetes.” 

In this study, the researchers found that IRE1α/XBP1 signaling axis also plays an important cell autonomous role in satellite cells.  Inducible deletion of IRE1α in satellite cells also inhibits myoblast fusion and myofiber hypertrophy in response to functional overload.

https://www.embopress.org/doi/full/10.1038/s44319-024-00197-4

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fthe-ire1-945-xbp1&filter=22