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The mitochondrial unfolded protein response (mtUPR) restores mitochondrial integrity after proteotoxic stress, but its control during physiological stress in aged muscle is unclear. In vivo and in vitro experiments compared young and older C57BL/6 mice exposed to treadmill running to exhaustion and used C2C12 myotubes under proteotoxic challenge. Running enhanced mtUPR markers in older animals with sex-biased effects, while oxidative damage and mtROS tuning altered mtUPR amplitude without changing mtROS alone. Redox-sensitive JNK-CHOP signaling emerged as the key regulator, supported by CHOP knockdown and JNK inhibition, linking oxidative and proteostatic burdens to mtUPR activation via a JNK-CHOP-dependent mechanism.",{"@graph":69,"@context":122},[70,84,105],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-redox-sensitive-jnk-chop-signaling-axis-drives-running-stress-induced-mtupr-activation-in-aged-skeletal-muscle/426816/",{"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-redox-sensitive-jnk-chop-signaling-axis-drives-running-stress-induced-mtupr-activation-in-aged-skeletal-muscle/426816.png","ImageObject",300,407,{"name":92,"@type":93},"jay","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-06","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study address about aging muscle?","Question",{"text":112,"@type":113},"It examines how mtUPR regulation changes during physiological stress in aged skeletal muscle, where control mechanisms remain poorly defined.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was running used in the in vivo experiments?",{"text":117,"@type":113},"Young and older C57BL/6 mice either stayed sedentary or performed three consecutive treadmill-running sessions to exhaustion as a mitochondrial stressor.",{"name":119,"@type":110,"acceptedAnswer":120},"What role does JNK-CHOP signaling play in mtUPR activation?",{"text":121,"@type":113},"Redox-sensitive JNK-CHOP signaling drives mtUPR activation under proteotoxic and running stress; CHOP knockdown and JNK inhibition confirmed this axis as mtROS-sensitive.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},426816,1790816552,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":14,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":24},3985747858866,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Innovation in Aging, 2025, Vol. 9, No. S2 1211  \nAbstract citation ID: igaf122.4054  \nA REDOX-SENSITIVE JNK-CHOP SIGNALING AXIS DRIVES RUNNING STRESS-INDUCED MTUPR ACTIVATION IN AGED SKELETAL MUSCLE  \nGrant Laskin, Baylah Mazonson, Yuhoung Kim, Laura Verdi, and Ladora Thompson, Boston University, Boston,  \nMassachusetts, United States  \nMitochondrial dysfunction and impaired proteostasis are aging hallmarks. The mitochondrial unfolded protein response (mtUPR) is a transcriptional program that restores mitochondrial integrity following proteotoxic stress, yet its regulation during physiological stress in aged muscle remains poorly defined. Here, we combine in vivo and in vitro approaches to investigate mtUPR regulation in aged skeletal muscle. Young (4-mo) and older (22-24-mo) C57BL/6 mice of both sexes either remained sedentary or performed three consecutive sessions of treadmill running to exhaustion as a physiological mitochondrial stressor. Running induced the putative mtUPR chaperones mtHsp70 in skeletal muscle of older mice and Hsp60 only in older males. mtUPR activation coincided with age-emergent indices of impaired mitochondrial proteostasis, most pronounced in males. Aged muscle exhibited modest carbonylation localized at intermyofibrillar mitochondria and running stress elevated 8-OHdG levels in males, suggesting greater oxidative burden in older males. To assess the role of mitochondrial reactive oxygen species (mtROS) in mtUPR activation, we induced mitochondrial matrix protein misfolding in C2C12 myotubes with or without an mtROS scavenger or stimulator. mtROS modulation amplified (stimulator) or suppressed (scavenger) the mtUPR during proteotoxic stress, but altering mtROS alone was insufficient to adjust mtUPR activation. Pathway screening revealed redox-sensitive activation of JNK-CHOP signaling, consistent with in vivo observations. Adenoviral-mediated shRNA CHOP knockdown and pharmacological JNK inhibition confirmed this axis as an mtROS-sensitive driver of the mtUPR. These findings support a model in which  \n1212 Innovation in Aging, 2025, Vol. 9, No. S2  \nproteostatic and oxidative burdens in aged muscle mitochondria, especially in males, potentiate physiological stress-induced mtUPR activation via a JNK-CHOP-dependent mechanism.","cbCaif8LrEOm1aX4","https://ap.wps.com/l/cbCaif8LrEOm1aX4","pdf",2080833,"English","# Abstract\n## Background\n## Methods\n## Key findings\n## Mechanistic pathway","[{\"question\":\"What problem does the study address about aging muscle?\",\"answer\":\"It examines how mtUPR regulation changes during physiological stress in aged skeletal muscle, where control mechanisms remain poorly defined.\"},{\"question\":\"How was running used in the in vivo experiments?\",\"answer\":\"Young and older C57BL/6 mice either stayed sedentary or performed three consecutive treadmill-running sessions to exhaustion as a mitochondrial stressor.\"},{\"question\":\"What role does JNK-CHOP signaling play in mtUPR activation?\",\"answer\":\"Redox-sensitive JNK-CHOP signaling drives mtUPR activation under proteotoxic and running stress; CHOP knockdown and JNK inhibition confirmed this axis as mtROS-sensitive.\"}]","A REDOX-SENSITIVE JNK-CHOP SIGNALING AXIS DRIVES RUNNING STRESS-INDUCED MTUPR ACTIVATION IN AGED SKELETAL MUSCLE | PDF",1790641900]