{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T02:42:48Z","timestamp":1783132968364,"version":"3.54.6"},"reference-count":47,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T00:00:00Z","timestamp":1643760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,5,1]]},"abstract":"<jats:p>Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium\u2013glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg\/kg\/day), could restore exercise training response in a model of hyperglycemia (low-dose streptozotocin [STZ]). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ-treated mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyperactivation of c-Jun N-terminal kinase (JNK)\/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK\/SMAD2 signaling with acute exercise was twofold higher in STZ compared with control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak, and impaired metabolic health (oral glucose tolerance test\u2013derived insulin sensitivity). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by cotherapy with SGLT2i.<\/jats:p>","DOI":"10.2337\/db21-0934","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T18:54:58Z","timestamp":1643828098000},"page":"881-893","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":20,"title":["Canagliflozin Prevents Hyperglycemia-Associated Muscle Extracellular Matrix Accumulation and Improves the Adaptive Response to Aerobic Exercise"],"prefix":"10.2337","volume":"71","author":[{"given":"Tara L.","family":"MacDonald","sequence":"first","affiliation":[{"name":"1Research Division, Joslin Diabetes Center, Boston, MA"},{"name":"2Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pattarawan","family":"Pattamaprapanont","sequence":"additional","affiliation":[{"name":"1Research Division, Joslin Diabetes Center, Boston, MA"},{"name":"2Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen M.","family":"Cooney","sequence":"additional","affiliation":[{"name":"1Research Division, Joslin Diabetes Center, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto C.","family":"Nava","sequence":"additional","affiliation":[{"name":"1Research Division, Joslin Diabetes Center, Boston, MA"},{"name":"2Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Mitri","sequence":"additional","affiliation":[{"name":"1Research Division, Joslin Diabetes Center, Boston, MA"},{"name":"2Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar","family":"Hafida","sequence":"additional","affiliation":[{"name":"1Research Division, Joslin Diabetes Center, Boston, MA"},{"name":"2Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4693-3191","authenticated-orcid":false,"given":"Sarah J.","family":"Lessard","sequence":"additional","affiliation":[{"name":"1Research Division, Joslin Diabetes Center, Boston, MA"},{"name":"2Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2022,2,2]]},"reference":[{"key":"2023052212402574700_B1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.pcad.2018.07.004","article-title":"The joint association of fitness and fatness on cardiovascular disease mortality: a meta-analysis","volume":"61","author":"Barry","year":"2018","journal-title":"Prog Cardiovasc Dis"},{"key":"2023052212402574700_B2","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1001\/jama.1989.03430170057028","article-title":"Physical fitness and all-cause mortality. A prospective study of healthy men and women","volume":"262","author":"Blair","year":"1989","journal-title":"JAMA"},{"key":"2023052212402574700_B3","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1056\/NEJM198811243192104","article-title":"Physical fitness as a predictor of cardiovascular mortality in asymptomatic North American men","volume":"319","author":"Ekelund","year":"1988","journal-title":"N Engl J Med"},{"key":"2023052212402574700_B4","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.amjcard.2011.11.031","article-title":"Cardiorespiratory fitness and metabolic risk","volume":"109","author":"Grundy","year":"2012","journal-title":"Am J Cardiol"},{"key":"2023052212402574700_B5","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.pcad.2014.09.011","article-title":"Physical activity and cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status","volume":"57","author":"Myers","year":"2015","journal-title":"Prog Cardiovasc Dis"},{"key":"2023052212402574700_B6","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1210\/jc.2009-1756","article-title":"Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function","volume":"95","author":"Nadeau","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2023052212402574700_B7","doi-asserted-by":"crossref","first-page":"3687","DOI":"10.1210\/jc.2008-2844","article-title":"Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity","volume":"94","author":"Nadeau","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"2023052212402574700_B8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s11154-012-9234-4","article-title":"Type 2 diabetes mellitus and exercise impairment","volume":"14","author":"Reusch","year":"2013","journal-title":"Rev Endocr Metab Disord"},{"key":"2023052212402574700_B9","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1001\/jamainternmed.2013.7783","article-title":"The influence of hyperglycemia on the therapeutic effect of exercise on glycemic control in patients with type 2 diabetes mellitus","volume":"173","author":"Solomon","year":"2013","journal-title":"JAMA Intern Med"},{"key":"2023052212402574700_B10","doi-asserted-by":"crossref","first-page":"921","DOI":"10.2337\/dc14-2813","article-title":"Association between cardiorespiratory fitness and the determinants of glycemic control across the entire glucose tolerance continuum","volume":"38","author":"Solomon","year":"2015","journal-title":"Diabetes Care"},{"key":"2023052212402574700_B11","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1152\/jappl.1999.87.3.1003","article-title":"Familial aggregation of VO(2max) response to exercise training: results from the HERITAGE Family Study","volume":"87","author":"Bouchard","year":"1999","journal-title":"J Appl Physiol (1985)"},{"key":"2023052212402574700_B12","doi-asserted-by":"crossref","first-page":"S446","DOI":"10.1097\/00005768-200106001-00013","article-title":"Individual differences in response to regular physical activity","volume":"33","author":"Bouchard","year":"2001","journal-title":"Med Sci Sports Exerc"},{"key":"2023052212402574700_B13","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1152\/physiolgenomics.00021.2013","article-title":"Selectively bred rat model system for low and high response to exercise training","volume":"45","author":"Koch","year":"2013","journal-title":"Physiol Genomics"},{"key":"2023052212402574700_B14","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.2337\/db13-0062","article-title":"Resistance to aerobic exercise training causes metabolic dysfunction and reveals novel exercise-regulated signaling networks","volume":"62","author":"Lessard","year":"2013","journal-title":"Diabetes"},{"key":"2023052212402574700_B15","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1038\/s42255-020-0240-7","article-title":"Hyperglycaemia is associated with impaired muscle signalling and aerobic adaptation to exercise","volume":"2","author":"MacDonald","year":"2020","journal-title":"Nat Metab"},{"key":"2023052212402574700_B16","doi-asserted-by":"crossref","first-page":"bvaa063","DOI":"10.1210\/jendso\/bvaa063","article-title":"Mechanistic causes of reduced cardiorespiratory fitness in type 2 diabetes","volume":"4","author":"Abushamat","year":"2020","journal-title":"J Endocr Soc"},{"key":"2023052212402574700_B17","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.2337\/dc07-0843","article-title":"Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes","volume":"30","author":"Bauer","year":"2007","journal-title":"Diabetes Care"},{"key":"2023052212402574700_B18","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.2337\/diacare.22.10.1640","article-title":"Effects of exercise training on oxygen uptake kinetic responses in women with type 2 diabetes","volume":"22","author":"Brandenburg","year":"1999","journal-title":"Diabetes Care"},{"key":"2023052212402574700_B19","doi-asserted-by":"crossref","first-page":"382","DOI":"10.2337\/diacare.17.5.382","article-title":"Muscle fiber composition and capillary density in women and men with NIDDM","volume":"17","author":"M\u00e5rin","year":"1994","journal-title":"Diabetes Care"},{"key":"2023052212402574700_B20","doi-asserted-by":"crossref","first-page":"851","DOI":"10.2337\/diab.33.9.851","article-title":"Influence of physical training on formation of muscle capillaries in type I diabetes","volume":"33","author":"Wallberg-Henriksson","year":"1984","journal-title":"Diabetes"},{"key":"2023052212402574700_B21","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1007\/s00125-018-4671-6","article-title":"SGLT inhibitor adjunct therapy in type 1 diabetes","volume":"61","author":"McCrimmon","year":"2018","journal-title":"Diabetologia"},{"key":"2023052212402574700_B22","doi-asserted-by":"crossref","first-page":"e123130","DOI":"10.1172\/jci.insight.123130","article-title":"SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms","volume":"4","author":"Osataphan","year":"2019","journal-title":"JCI Insight"},{"key":"2023052212402574700_B23","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1007\/s00125-018-4654-7","article-title":"Development of SGLT1 and SGLT2 inhibitors","volume":"61","author":"Rieg","year":"2018","journal-title":"Diabetologia"},{"key":"2023052212402574700_B24","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1038\/s41598-018-19658-7","article-title":"Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH","volume":"8","author":"Shiba","year":"2018","journal-title":"Sci Rep"},{"key":"2023052212402574700_B25","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.2147\/DMSO.S212003","article-title":"Sodium-glucose cotransporter-2 (SGLT2) inhibitors: a clinician\u2019s guide","volume":"12","author":"Simes","year":"2019","journal-title":"Diabetes Metab Syndr Obes"},{"key":"2023052212402574700_B26","doi-asserted-by":"crossref","first-page":"6611","DOI":"10.1073\/pnas.1705845114","article-title":"Dapagliflozin suppresses glucagon signaling in rodent models of diabetes","volume":"114","author":"Wang","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2023052212402574700_B27","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1210\/jc.2018-01741","article-title":"Influence of sodium glucose cotransporter 2 inhibition on physiological adaptation to endurance exercise training","volume":"104","author":"Newman","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2023052212402574700_B28","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.metabol.2019.05.009","article-title":"The combination of exercise training and sodium-glucose cotransporter-2 inhibition improves glucose tolerance and exercise capacity in a rodent model of type 2 diabetes","volume":"97","author":"Linden","year":"2019","journal-title":"Metabolism"},{"key":"2023052212402574700_B29","doi-asserted-by":"crossref","first-page":"E492","DOI":"10.1152\/ajpendo.00401.2019","article-title":"Combined effect of canagliflozin and exercise training on high-fat diet-fed mice","volume":"318","author":"Tanaka","year":"2020","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2023052212402574700_B30","doi-asserted-by":"crossref","first-page":"e0148010","DOI":"10.1371\/journal.pone.0148010","article-title":"Graded maximal exercise testing to assess mouse cardio-metabolic phenotypes","volume":"11","author":"Petrosino","year":"2016","journal-title":"PLoS One"},{"key":"2023052212402574700_B31","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1038\/s41467-018-05439-3","article-title":"JNK regulates muscle remodeling via myostatin\/SMAD inhibition","volume":"9","author":"Lessard","year":"2018","journal-title":"Nat Commun"},{"key":"2023052212402574700_B32","doi-asserted-by":"crossref","first-page":"e000124","DOI":"10.1136\/bmjdrc-2015-000124","article-title":"Type 2 diabetes exaggerates exercise effort and impairs exercise performance in older women","volume":"3","author":"Huebschmann","year":"2015","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2023052212402574700_B33","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1139\/H07-144","article-title":"Impact of metformin on peak aerobic capacity","volume":"33","author":"Braun","year":"2008","journal-title":"Appl Physiol Nutr Metab"},{"key":"2023052212402574700_B34","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1111\/dom.13309","article-title":"Effects of empagliflozin on cardiorespiratory fitness and significant interaction of loop diuretics","volume":"20","author":"Carbone","year":"2018","journal-title":"Diabetes Obes Metab"},{"key":"2023052212402574700_B35","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1139\/cjpp-2018-0359","article-title":"Empagliflozin improves cardiorespiratory fitness in type 2 diabetes: translational implications","volume":"96","author":"Kumar","year":"2018","journal-title":"Can J Physiol Pharmacol"},{"key":"2023052212402574700_B36","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.2337\/diacare.28.12.2877","article-title":"Rosiglitazone improves exercise capacity in individuals with type 2 diabetes","volume":"28","author":"Regensteiner","year":"2005","journal-title":"Diabetes Care"},{"key":"2023052212402574700_B37","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1097\/MNH.0000000000000584","article-title":"Renal effects of SGLT2 inhibitors: an update","volume":"29","author":"Nespoux","year":"2020","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"2023052212402574700_B38","doi-asserted-by":"crossref","first-page":"501","DOI":"10.2337\/dc19-1410","article-title":"Reinterpreting cardiorenal protection of renal sodium-glucose cotransporter 2 inhibitors via cellular life history programming","volume":"43","author":"Avogaro","year":"2020","journal-title":"Diabetes Care"},{"key":"2023052212402574700_B39","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.2337\/dc16-0330","article-title":"CV protection in the EMPA-REG OUTCOME Trial: a \u201cthrifty substrate\u201d hypothesis","volume":"39","author":"Ferrannini","year":"2016","journal-title":"Diabetes Care"},{"key":"2023052212402574700_B40","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s11897-021-00529-8","article-title":"SGLT2 inhibitors and their mode of action in heart failure\u2014has the mystery been unravelled?","volume":"18","author":"Pabel","year":"2021","journal-title":"Curr Heart Fail Rep"},{"key":"2023052212402574700_B41","doi-asserted-by":"crossref","first-page":"e0167790","DOI":"10.1371\/journal.pone.0167790","article-title":"Inter-individual variability in the adaptive responses to endurance and sprint interval training: a randomized crossover study","volume":"11","author":"Bonafiglia","year":"2016","journal-title":"PLoS One"},{"key":"2023052212402574700_B42","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1113\/JP273480","article-title":"Refuting the myth of non-response to exercise training: \u2018non-responders\u2019 do respond to higher dose of training","volume":"595","author":"Montero","year":"2017","journal-title":"J Physiol"},{"key":"2023052212402574700_B43","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1007\/s00125-017-4461-6","article-title":"Exercise training response heterogeneity: physiological and molecular insights","volume":"60","author":"Sparks","year":"2017","journal-title":"Diabetologia"},{"key":"2023052212402574700_B44","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1152\/japplphysiol.01295.2009","article-title":"Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans","volume":"108","author":"Timmons","year":"2010","journal-title":"J Appl Physiol (1985)"},{"key":"2023052212402574700_B45","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.1113\/JP272559","article-title":"Genomic and transcriptomic predictors of response levels to endurance exercise training","volume":"595","author":"Sarzynski","year":"2017","journal-title":"J Physiol"},{"key":"2023052212402574700_B46","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1741-7007-3-19","article-title":"Modulation of extracellular matrix genes reflects the magnitude of physiological adaptation to aerobic exercise training in humans","volume":"3","author":"Timmons","year":"2005","journal-title":"BMC Biol"},{"key":"2023052212402574700_B47","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.2337\/db19-1180","article-title":"Exercise-induced increases in insulin sensitivity after bariatric surgery are mediated by muscle extracellular matrix remodeling","volume":"69","author":"Dantas","year":"2020","journal-title":"Diabetes"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/71\/5\/881\/704511\/db210934.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/71\/5\/881\/704511\/db210934.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T12:41:44Z","timestamp":1684759304000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/71\/5\/881\/141060\/Canagliflozin-Prevents-Hyperglycemia-Associated"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,2]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,2,2]]},"published-print":{"date-parts":[[2022,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db21-0934","relation":{},"ISSN":["0012-1797"],"issn-type":[{"value":"0012-1797","type":"print"}],"subject":[],"published":{"date-parts":[[2022,2,2]]}}}