{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:28:02Z","timestamp":1791412082839,"version":"4.3.3"},"reference-count":76,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,4]],"date-time":"2024-02-04T00:00:00Z","timestamp":1707004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities of China","doi-asserted-by":"publisher","award":["2021TD012"],"award-info":[{"award-number":["2021TD012"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities of China","doi-asserted-by":"publisher","award":["Dnr 2019-01567"],"award-info":[{"award-number":["Dnr 2019-01567"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities of China","doi-asserted-by":"publisher","award":["Dnr 2022-01129"],"award-info":[{"award-number":["Dnr 2022-01129"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities of China","doi-asserted-by":"publisher","award":["Dnr 20190514"],"award-info":[{"award-number":["Dnr 20190514"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2021TD012"],"award-info":[{"award-number":["2021TD012"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["Dnr 2019-01567"],"award-info":[{"award-number":["Dnr 2019-01567"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["Dnr 2022-01129"],"award-info":[{"award-number":["Dnr 2022-01129"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["Dnr 20190514"],"award-info":[{"award-number":["Dnr 20190514"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003173","name":"Crafoord Foundation","doi-asserted-by":"publisher","award":["2021TD012"],"award-info":[{"award-number":["2021TD012"]}],"id":[{"id":"10.13039\/501100003173","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003173","name":"Crafoord Foundation","doi-asserted-by":"publisher","award":["Dnr 2019-01567"],"award-info":[{"award-number":["Dnr 2019-01567"]}],"id":[{"id":"10.13039\/501100003173","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003173","name":"Crafoord Foundation","doi-asserted-by":"publisher","award":["Dnr 2022-01129"],"award-info":[{"award-number":["Dnr 2022-01129"]}],"id":[{"id":"10.13039\/501100003173","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003173","name":"Crafoord Foundation","doi-asserted-by":"publisher","award":["Dnr 20190514"],"award-info":[{"award-number":["Dnr 20190514"]}],"id":[{"id":"10.13039\/501100003173","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db\/db mice (D) by comparison with control m\/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 \u00b1 0.45 mmol L\u22121 vs. 4.26 \u00b1 0.6 mmol L\u22121, p &lt; 0.05), grip strength (D vs. W: 166.87 \u00b1 15.19 g vs. 191.76 \u00b1 14.13 g, p &lt; 0.05), exercise time (D vs. W: 1082.38 \u00b1 104.67 s vs. 1716 \u00b1 168.55 s, p &lt; 0.05) and exercise speed to exhaustion (D vs. W: 24.25 \u00b1 2.12 m min\u22121 vs. 34.75 \u00b1 2.66 m min\u22121, p &lt; 0.05), GAS wet weight (D vs. W: 0.07 \u00b1 0.01 g vs. 0.13 \u00b1 0.01 g, p &lt; 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 \u00b1 0.01% vs. 0.54 \u00b1 0.02%, p &lt; 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 \u00b1 368.19 \u00b5m2 vs. 2747.83 \u00b1 406.44 \u00b5m2, p &lt; 0.05). We found that both MCC950 (10 mg kg\u22121) treatment and exercise improved the atrophic parameters that had deteriorated in the db\/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 \u00b1 310.97 vs. 1974.67 \u00b1 326.15 \u00b5m2, p &lt; 0.05) or exercise only (DE) (DEI vs. DE: 2597 \u00b1 310.97 vs. 2006.33 \u00b1 263.468 \u00b5m2, p &lt; 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db\/db mice and for the complete implementation of the exercise intervention, we used relatively young db\/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.<\/jats:p>","DOI":"10.3390\/molecules29030712","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T05:36:43Z","timestamp":1707197803000},"page":"712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise"],"prefix":"10.3390","volume":"29","author":[{"given":"Xiaoyu","family":"Yan","sequence":"first","affiliation":[{"name":"Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China"},{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"},{"name":"Department of Physical Education, Northwestern Polytechnical University, Xi\u2019an 710072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China"},{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Ling","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewis","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences in Malm\u00f6, Lund University Diabetes Centre, Lund University, 21428 Malm\u00f6, Sweden"},{"name":"NanoLund Center for NanoScience, Lund University, 22100 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weicheng","family":"Hua","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"},{"name":"School of Life Sciences, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boxuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"},{"name":"School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6261-9827","authenticated-orcid":false,"given":"Yujia","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Sport Science, Beijing Sport University, Beijing 100084, China"},{"name":"Institute of Physical Education, Jiangsu Normal University, Xuzhou 221116, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3502-0901","authenticated-orcid":false,"given":"Lijing","family":"Gong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Exercise and Physical Fitness of Ministry of Education, Beijing Sport University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0401-4608","authenticated-orcid":false,"given":"Enming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences in Malm\u00f6, Lund University Diabetes Centre, Lund University, 21428 Malm\u00f6, Sweden"},{"name":"NanoLund Center for NanoScience, Lund University, 22100 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"917113","DOI":"10.3389\/fendo.2022.917113","article-title":"Diabetic muscular atrophy: Molecular mechanisms and promising therapies","volume":"13","author":"Shen","year":"2022","journal-title":"Front. 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