University of Houston researchers discover key mechanism for skeletal muscle regeneration

Newly published research from the University of Houston College of Pharmacy identifies key mechanisms of skeletal muscle regeneration and growth following resistance exercise. This finding opens the door to developing targeted therapies for various muscle disorders, such as Muscular Dystrophy, which affect millions worldwide.

Skeletal muscles are formed during embryonic development by the fusion of specialized cells called myoblasts. Adult skeletal muscles maintain regenerative capacity due to the presence of muscle stem cells, named satellite cells. After injury, satellite cells proliferate and differentiate into myoblasts, which fuse with each other and injured myofibers to accomplish muscle regeneration. In many muscular disorders, this intrinsic capacity is diminished, resulting in loss of muscle mass and function.

UH researchers found that Inositol-requiring enzyme 1 (IRE1), 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 Ashok Kumar, Else and Philip Hargrove Endowed Professor of pharmacy in the Department of Pharmacological and Pharmaceutical Sciences at the UH College of Pharmacy, in EMBO Reports.

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

Aniket Joshi, a graduate student in Kumar’s lab and first author on the article, emphasized the significance: "Size is very important for muscle. Muscle grows only in size, not in number. 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."

This new research builds on previous work from Kumar’s team. In 2021, research from Kumar’s lab published in ELife described the role of the IRE1α/XBP1 signaling axis in regenerating healthy skeletal muscle after acute injury and in models of Duchenne Muscular Dystrophy.

Along with Kumar and Joshi, post-doctoral fellow Meiricris Tomaz da Silva and research assistant professor Anirban Roy conducted this research at UH. Other authors include Micah Castillo, Preethi Gunaratne, Mingfu Wu, Yu Liu; former post-doctoral fellow Tatiana E. Koike; and Takao Iwawaki from Kanazawa Medical University in Japan.