{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:59:08Z","timestamp":1787018348682,"version":"build-2736575974"},"reference-count":68,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21 AG045634,R01 AG063661,R01 HL61912,P30AG021334"],"award-info":[{"award-number":["R21 AG045634,R01 AG063661,R01 HL61912,P30AG021334"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Johns Hopkins University","award":["Clarence Doodeman Endowment in Cardiology"],"award-info":[{"award-number":["Clarence Doodeman Endowment in Cardiology"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,15]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Here, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 \u00b1 2.7 years, mean \u00b1 SEM), nonfrail older (NFO) individuals (79 \u00b1 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 \u00b1 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with\n                      <jats:sup>31<\/jats:sup>\n                      P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO\n                      <jats:sub>2<\/jats:sub>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      During graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by\n                      <jats:sup>31<\/jats:sup>\n                      P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Several-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>This work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.141246","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T12:07:34Z","timestamp":1600344454000},"source":"Crossref","is-referenced-by-count":59,"title":["Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty"],"prefix":"10.1172","volume":"5","author":[{"given":"Sabra C.","family":"Lewsey","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4295-4585","authenticated-orcid":true,"given":"Kilian","family":"Weiss","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, and"},{"name":"Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"name":"Philips Healthcare Germany, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7044-9941","authenticated-orcid":true,"given":"Michael","family":"Sch\u00e4r","sequence":"additional","affiliation":[{"name":"Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."},{"name":"Key Laboratory for Biomedical Engineering of Ministry of Education, Department of Biomedical Engineering, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0071-0155","authenticated-orcid":true,"given":"Paul A.","family":"Bottomley","sequence":"additional","affiliation":[{"name":"Division of Magnetic Resonance Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7638-1864","authenticated-orcid":true,"given":"T. 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