{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Calpain‐3 (CAPN3), also known as p94, is a skeletal muscle–specific, Ca²⁺‐dependent cysteine protease that plays a central role in sarcomere integrity and cytoskeletal remodeling. It is uniquely characterized by its rapid autolytic activity and its ability to undergo intermolecular complementation, features that enable CAPN3 to act as a “modulator protease” regulating the proteolytic processing of key myofibrillar components."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " CAPN3 is found in close proximity to titin (connectin) at the sarcomere, where it interacts with multiple binding sites, including regions in titin’s N2A and M-line segments. Through these interactions, CAPN3 not only becomes incorporated into the structural scaffold of the myofibril but also exerts a regulatory influence by cleaving substrates such as titin itself, filamin C, and AHNAK – a process that is important for maintaining cytoskeletal architecture and enabling adaptive responses to mechanical stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " In addition, CAPN3 activity facilitates proper sarcomere remodeling by promoting the turnover of damaged proteins via pathways upstream of the ubiquitin-proteasome system, thereby ensuring muscle homeostasis and efficient repair under conditions of increased mechanical load."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, CAPN3 appears to stabilize multi‐protein complexes at sites of force transmission, as its interactions with titin and other structural proteins help preserve the dynamic balance between assembly and disassembly of the sarcomere; defects in these processes underlie the pathogenesis of limb‐girdle muscular dystrophy type 2A (LGMD2A)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mathieu Taveau, Nathalie Bourg, Guillaume Sillon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain 3 is activated through autolysis within the active site and lyses sarcomeric and sarcolemmal components."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.23.24.9127-9135.2003"}], "href": "https://doi.org/10.1128/MCB.23.24.9127-9135.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14645524"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14645524"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yasuko Ono, Koichi Ojima, Fumiko Shinkai-Ouchi, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Multiple molecular interactions implicate the connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M708262200"}], "href": "https://doi.org/10.1074/jbc.M708262200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18310072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18310072"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yasuko Ono, Kazumi Kakinuma, Fukuyo Torii, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddn081"}], "href": "https://doi.org/10.1093/hmg/ddn081"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18334579"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18334579"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Irina Kramerova, Elena Kudryashova, Gayathri Venkatraman, et al. 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