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The study links the RETREG1/FAM134B system to both shaping ER morphology and degrading ER membranes. During differentiation, the RETREG1/FAM134B1 isoform is lysosomally degraded and replaced by RETREG1/FAM134B2, a shortened variant retaining the functional C-terminal LIR but losing part of the RHD. Restoring Retreg1/Fam134b2 in knockout myoblasts rescues ER proteomic abnormalities and prevents ER dilation, while Retreg1/Fam134b1 only partially rescues. Reticulophagy flux increases during cell fusion and returns to baseline after maturation.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-retreg1fam134b-isoform-switch-regulates-reticulophagy-during-myogenesis/418787/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-retreg1fam134b-isoform-switch-regulates-reticulophagy-during-myogenesis/418787.png","ImageObject",300,407,{"name":92,"@type":93},"Quinn Holloway","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What isoform switch occurs during myoblast differentiation?","Question",{"text":113,"@type":114},"After differentiation, RETREG1/FAM134B1 undergoes lysosomal degradation and is progressively replaced by the shorter RETREG1/FAM134B2 isoform.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does RETREG1/FAM134B2 differ from RETREG1/FAM134B1?",{"text":118,"@type":114},"RETREG1/FAM134B2 is truncated: it lacks the N-terminal domain and part of the reticulon homology domain, while retaining the identical C-terminal region including the functional LIR.",{"name":120,"@type":111,"acceptedAnswer":121},"When is reticulophagy flux highest during myogenesis?",{"text":122,"@type":114},"Reticulophagy flux remains low in proliferating myoblasts, rises rapidly as cells begin to fuse, peaks at the height of cell fusion, and returns to basal levels after myotube maturation.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},418787,1791070187,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":81,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":39,"preview_page_count":4},2336474466712,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","AUTOPHAGY  \n2025, VOL. 21, NO. 12, 3413–3415  \n[https://doi.org/10.1080/15548627.2025.2494803](https://doi.org/10.1080/15548627.2025.2494803)  \nRESEARCH PAPER     \nA RETREG1/FAM134B isoform switch regulates reticulophagy during myogenesis  \nViviana Buonomoa,b, Michele Cilloa,b, and Paolo Grumati a,b  \naTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; bDepartment of Clinical Medicine and Surgery, Federico II University, Naples, Italy  \nABSTRACT  \nDuring 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 Retreg1/Fam134b2 in retreg1/fam134bknockout myoblasts is both necessary and sufficient to rescue the abnormal proteomic landscape and prevent ER dilation. Conversely, the re-expression of Retreg1/Fam134b1 only partially rescues ER defects. We highlighted the role of RETREG1/FAM134B isoforms and reticulophagy in maintaining proper ER dynamics during myogenesis.  \nARTICLE HISTORY  \nReceived 17 March 2025 Revised 9 April 2025 Accepted 13 April 2025  \nKEYWORDS  \nAutophagy; FAM134B; myogenesis; reticulophagy; RETREG1  \nThe endoplasmic reticulum (ER) has the intrinsic ability toremodel its shape and size in response to cellular stimuli that occur throughout an organism’s lifespan. ER morphology is tuned by resident proteins and external forces that drive membrane bending, tubulation and vesiculation. Moreover, the elaborate and dynamic structure of the ER is linked to its functional roles within the cell. Each cell type has specialized functions that require well-defined ER morphology and protein composition.  \nReticulophagy, the selective autophagic degradation of the ER, plays a key role in ER membrane remodeling. This process requires fragmentation ofthe ER network into discrete portions for delivery to lysosomes. Reticulophagy receptors, like the RETREG family and RTN3, contribute to the membrane remodeling through their reticulon homology domain (RHD). Additionally, their LC3-interacting region (LIR) enables them to interact with the autophagy machinery, ensuring that the fragmentation and turnover of ER membranes are in lockstep. During myogenesis the ER undergoes extensive structural and proteomic reorganization to form the sarcoplasmic reticulum (SR) . Single ERs, from individual myoblasts, fuse to generate a unified SR within myotubes. The molecular mechanisms behind the shaping of the ER network throughout this process are still unclear. Therefore, we investigated the temporal dynamics of ER remodeling during myogenesis. We compared the full proteomes of undifferentiated myoblasts and differentiated myotubes highlighting significant alterations in the proteomic landscape of the ER, along with a notable enrichment of proteins associated with the lysosomal pathway. Therefore, we investigated whether  \nreticulophagy plays a role in myoblast differentiation. We monitored reticulophagy flux during myoblast differentiation over 12 days. We noticed that in proliferating myoblasts, reticulophagy flux was maintained at a low basal level. As cells began to fuse, reticulophagy flux rapidly increases, peaking at the height of cell fusion and returning to its initial basal level after myotubes maturation.  \nWe ide","cbCais9Oi2dFPefn","https://ap.wps.com/l/cbCais9Oi2dFPefn","pdf",511107,"English","# Abstract\n# Background: ER remodeling and reticulophagy\n# Reticulophagy dynamics during myoblast differentiation\n# RETREG1/FAM134B isoform switching and regulation","[{\"question\":\"What isoform switch occurs during myoblast differentiation?\",\"answer\":\"After differentiation, RETREG1/FAM134B1 undergoes lysosomal degradation and is progressively replaced by the shorter RETREG1/FAM134B2 isoform.\"},{\"question\":\"How does RETREG1/FAM134B2 differ from RETREG1/FAM134B1?\",\"answer\":\"RETREG1/FAM134B2 is truncated: it lacks the N-terminal domain and part of the reticulon homology domain, while retaining the identical C-terminal region including the functional LIR.\"},{\"question\":\"When is reticulophagy flux highest during myogenesis?\",\"answer\":\"Reticulophagy flux remains low in proliferating myoblasts, rises rapidly as cells begin to fuse, peaks at the height of cell fusion, and returns to basal levels after myotube maturation.\"}]","A RETREG1/FAM134B isoform switch regulates reticulophagy during myogenesis | PDF",1790614350]