Inositol-requiring enzyme 1 alpha (IRE1α) may play a critical role in regulating the regeneration of skeletal muscles by controlling the expression of myostatin, according to a new study published in The Journal of Clinical Investigation. Therefore, modulating IRE1α may be a potential new therapeutic approach in degenerative muscle diseases such as Duchenne muscular dystrophy (DMD).

Myostatin, a key negative regulator of muscle repair and growth, is a valuable target to improve muscle health in mouse models of muscular dystrophy. IRE1 is a stress sensor that plays a role in controlling stress responses during tissue injury and regeneration. 

In the present study, a team of researchers led by Yong Liu, PhD, showed that IRE1α regulates skeletal muscle regeneration in response to injury and muscular dystrophy through the regulated IRE1-dependent decay (RIDD) of mRNA encoding myostatin.

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“Our findings demonstrate the physiological importance of IRE1α’s RIDD activity in the control of muscle regeneration,” the researchers wrote and added that the dysregulation of IRE1α may represent an unknown mechanism linking cellular stress to muscle degenerative diseases.

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The researchers first showed, using a mouse model, that IRE1α was activated during muscle regeneration induced by injury. When they ablated IRE1α in muscles, regeneration following injury was impaired, as expected. 

They then conducted loss-of-function and gain-of-function experiments in myocytes and showed that IRE1α controls myoblast differentiation and myotube hypertrophy through the RIDD pathway of myostatin mRNA.

Finally, when they used mdx mice (the most widely used mouse model of DMD) that were deficient for IRE1α in their muscles, they saw that myostatin signaling was increased and the dystrophic phenotype was worsened. 

“Thus, these results reveal a pivotal role for the RIDD output of IRE1α in muscle regeneration, offering new insight into potential therapeutic strategies for muscle loss diseases, “ the researchers concluded.

Reference

He S, Fu T, Yu Y, et al. IRE1α regulates skeletal muscle regeneration through Myostatin mRNA decay. J Clin Invest. Published online July 20, 2021. doi:10.1172/JCI143737

Neurologists Neuromuscular Disorders