Overexpression of Rtl1 via synonymous mutation silencing miRNA target site drives skeletal muscle hypertrophy and...

The retrovirus-derived Rtl1 gene is integral to skeletal muscle development. However, the underlying mechanisms and functional roles of Rtl1 in skeletal muscle growth remain unclear.

We generated conditional overexpression of Rtl1 in mice via synonymous mutations that silence seven miRNA target sites, thereby efficiently abolishing miRNA-mediated inhibition in vivo. This conditional, specific overexpression of synonymous mutated Rtl1 (mRtl1) in the diaphragm muscles of mice foetuses resulted in aberrant embryonic diaphragm muscle development, adversely affecting both diaphragmatic and pulmonary development. This modification ultimately culminated in severe respiratory distress, leading to postnatal mortality. Subsequently, the conditional overexpression of mRtl1 in the tibialis anterior muscle of adult mice resulted in inflammation and hypertrophy. Furthermore, the overexpression of mRtl1 in cultured myotubes activated the TLR7/8-NFκB and Jak-STAT3 signalling pathways, resulting in hypertrophy and inflammation.

These findings suggest that the overexpression of Rtl1 may contribute to skeletal muscle hypertrophy and induce inflammation in murine models. Consequently, the precise regulation of Rtl1 expression is essential for maintaining skeletal muscle function.