{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPRKAG3 encodes the muscle‐specific γ3 regulatory subunit of AMP‐activated protein kinase (AMPK), a key enzyme governing cellular and whole‐body energy homeostasis. Early work in pigs revealed that a nonconservative mutation (R200Q) in PRKAG3 leads to high glycogen content in skeletal muscle—an alteration that has both beneficial effects on meat content and adverse effects on processing yield—and has been linked mechanistically to impaired glycogen synthesis, drawing parallels with yeast SNF4 loss‐of‐function phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nInvestigations using various PRKAG3 mutations in animal models and human subjects have elucidated its critical role in modulating skeletal muscle metabolism, especially during and after exercise. Gain‐of‐function mutations—such as the human R225W variant—result in elevated AMPK activity, enhanced acetyl‐CoA carboxylase phosphorylation, shifts toward lipid oxidation, and improved postexercise glucose uptake and glycogen resynthesis. These studies underscore the isoform’s importance for initiating metabolic and gene regulatory responses that fine‐tune muscle energy utilization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical characterizations have shown that AMPK complexes containing the γ3 isoform display distinct nucleotide binding properties and regulatory behaviors compared to other γ isoforms. Expression studies have confirmed that PRKAG3 is highly enriched in white, fast‐twitch skeletal muscle fibers, reinforcing its specialized role in muscle metabolism. Moreover, genetic variance in PRKAG3 is being linked to broader metabolic and regulatory phenotypes—including associations with noninsulin‐dependent diabetes mellitus, polycystic ovary syndrome, aberrant weight gain during antipsychotic treatment, alterations in cancer metabolism, and even cardiac conduction anomalies—suggesting that isoform‐specific targeting of AMPK may offer novel therapeutic avenues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "D Milan, J T Jeon, C Looft, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Changes in exercise-induced gene expression in 5'-AMP-activated protein kinase gamma3-null and gamma3 R225Q transgenic mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/diabetes.54.12.3484"}], "href": "https://doi.org/10.2337/diabetes.54.12.3484"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16306365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16306365"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kerstin Lindgren, Mattias Ormestad, Mårten Persson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of the muscle-specific AMP-activated protein kinase alpha2beta2gamma3 complexes by AMP and implications of the mutations in the gamma3-subunit for the AMP dependence of the enzyme."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1742-4658.2007.05821.x"}], "href": "https://doi.org/10.1111/j.1742-4658.2007.05821.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17518971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17518971"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sheila R Costford, Nihan Kavaslar, Nadav Ahituv, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gain-of-function R225W mutation in human AMPKgamma(3) causing increased glycogen and decreased triglyceride in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0000903"}], "href": "https://doi.org/10.1371/journal.pone.0000903"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17878938"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17878938"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "S A Crawford, S R Costford, C Aguer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)gamma(3) results in increased oxidative capacity and glucose uptake in human primary myotubes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-010-1788-7"}], "href": "https://doi.org/10.1007/s00125-010-1788-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20473479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20473479"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kohei Kido, Nicolas O Eskesen, Nicolai S Henriksen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMPKγ3 Controls Muscle Glucose Uptake in Recovery From Exercise to Recapture Energy Stores."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db23-0358"}], "href": "https://doi.org/10.2337/db23-0358"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37506328"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37506328"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "P Weyrich, F Machicao, H Staiger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of AMP-activated protein kinase gamma 3 genetic variability in glucose and lipid metabolism in non-diabetic whites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-007-0788-8"}], "href": "https://doi.org/10.1007/s00125-007-0788-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17701023"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17701023"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Kari Sproul, Michelle R Jones, Ricardo Azziz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association study of AMP-activated protein kinase subunit genes in polycystic ovary syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Endocrinol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/EJE-09-0245"}], "href": "https://doi.org/10.1530/EJE-09-0245"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19574280"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19574280"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Lata Ramanathan, Payal R Sheth, Polina Ogas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Purification and characterization of truncated human AMPK alpha 2 beta 2 gamma 3 heterotrimer from baculovirus-infected insect cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Expr Purif (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pep.2009.10.007"}], "href": "https://doi.org/10.1016/j.pep.2009.10.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19836452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19836452"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "G Jassim, J Fernø, F M Theisen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacopsychiatry (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1055/s-0030-1263174"}], "href": "https://doi.org/10.1055/s-0030-1263174"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20821366"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20821366"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Aaron E Hoffman, Kathryn Demanelis, Alan Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of AMP-activated protein kinase with risk and progression of non-Hodgkin lymphoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Epidemiol Biomarkers Prev (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1055-9965.EPI-12-1014"}], "href": "https://doi.org/10.1158/1055-9965.EPI-12-1014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23396962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23396962"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ken-Pen Weng, Yeong-Seng Yuh, Shih-Hui Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PRKAG3 polymorphisms associated with sporadic Wolff-Parkinson-White syndrome among a Taiwanese population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Chin Med Assoc (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jcma.2016.08.008"}], "href": "https://doi.org/10.1016/j.jcma.2016.08.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27866917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27866917"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Robin Willows, Naveenan Navaratnam, Ana Lima, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Association of breast cancer risk and the mTOR pathway in women of African ancestry in 'The Root' Consortium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgx055"}], "href": "https://doi.org/10.1093/carcin/bgx055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28582508"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28582508"}]}]}]}