A RETREG1/FAM134B isoform switch regulates reticulophagy during myogenesis

During skeletal muscle development, the sarcoplasmic reticulum forms through the homotypic fusion of ER membranes from individual myoblasts. This involves significant ER remodeling, characterized by an overhaul of its proteomic landscape and the activation of reticulophagy. We described how RETREG1/FAM134B is implicated in both shaping ER morphology and degrading ER membranes through reticulophagy. Following myoblast differentiation, the classic RETREG1/FAM134B1 undergoes lysosomal degradation and is progressively replaced by the shorter RETREG1/FAM134B2 isoform. RETREG1/FAM134B2 is a truncated variant of RETREG1/FAM134B1 maintaining an identical C-terminal region, including the functional LIR, but with a partial loss of its reticulon homology domain. The switch between these two isoforms plays a crucial role in ER morphology and muscle development. Re-expressing <i>Retreg1/Fam134b2</i> in <i>retreg1/fam134b</i>-knockout myoblasts is both necessary and sufficient to rescue the abnormal proteomic landscape and prevent ER dilation. Conversely, the re-expression of <i>Retreg1/Fam134b1</i> only partially rescues ER defects. We highlighted the role of RETREG1/FAM134B isoforms and reticulophagy in maintaining proper ER dynamics during myogenesis.