{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSarcalumenin (SAR) is a high‐capacity Ca²⁺‐binding protein localized in the sarcoplasmic reticulum (SR) of striated muscle cells, where it plays a pivotal role in regulating intracellular Ca²⁺ cycling. Studies in SAR‐deficient mice have revealed that, although basal muscle force generation may be maintained, the absence of SAR leads to slower relaxation phases after contraction and compromised Ca²⁺ uptake into the SR, ultimately impairing overall Ca²⁺ homeostasis in both skeletal and cardiac muscle cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn skeletal muscle, loss of SAR triggers compensatory mechanisms that affect Ca²⁺ regulatory proteins. For example, enhanced store‐operated Ca²⁺ entry (SOCE) was observed in SAR knockout mice along with an increased expression of MG29, a protein associated with the triad junction. This compensatory adjustment correlated with greater resistance to muscle fatigue under intermittent stimulation. In the heart, SAR deficiency leads to impaired Ca²⁺ reuptake through downregulation of critical proteins like SERCA2a, which becomes particularly detrimental under physiological stress such as endurance exercise or in the aging heart, eventually contributing to signs of heart failure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditionally, complementary research has highlighted that transcriptional regulators such as Six1 play essential roles in muscle phenotype determination. Overexpression of Six1 in muscle cells not only upregulates fast-twitch muscle-specific genes but also modulates cell cycle progression, thereby influencing muscle fiber composition and function. These findings suggest that the adaptive responses in muscle physiology involve both the intricate regulation of Ca²⁺ handling by proteins like SAR and transcriptional programs controlled by factors like Six1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Morikatsu Yoshida, Susumu Minamisawa, Miei Shimura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired Ca2+ store functions in skeletal and cardiac muscle cells from sarcalumenin-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M406618200"}], "href": "https://doi.org/10.1074/jbc.M406618200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15569689"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15569689"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Miei Shimura, Susumu Minamisawa, Hiroshi Takeshima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvm019"}], "href": "https://doi.org/10.1093/cvr/cvm019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18006473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18006473"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiaoli Zhao, Morikatsu Yoshida, Leticia Brotto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhanced resistance to fatigue and altered calcium handling properties of sarcalumenin knockout mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Physiol Genomics (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/physiolgenomics.00020.2005"}], "href": "https://doi.org/10.1152/physiolgenomics.00020.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15998745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15998745"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Qibin Jiao, Yunzhe Bai, Toru Akaike, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sarcalumenin is essential for maintaining cardiac function during endurance exercise training."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00946.2008"}], "href": "https://doi.org/10.1152/ajpheart.00946.2008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19502553"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19502553"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Qibin Jiao, Hiroshi Takeshima, Yoshihiro Ishikawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sarcalumenin plays a critical role in age-related cardiac dysfunction due to decreases in SERCA2a expression and activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Calcium (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ceca.2011.10.003"}], "href": "https://doi.org/10.1016/j.ceca.2011.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22119571"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22119571"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Wangjun Wu, Zhuqing Ren, Lin Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of Six1 gene suppresses proliferation and enhances expression of fast-type muscle genes in C2C12 myoblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-013-1653-3"}], "href": "https://doi.org/10.1007/s11010-013-1653-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23613228"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23613228"}]}]}]}