Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress.
Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress.
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DOI：
10.1172/jci.insight.155147
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发表时间：
2022-12-22
期刊：
影响因子：
8
通讯作者：
Perry, Christopher G. R.
中科院分区：
文献类型：
--
作者：
Delfinis, Luca J.;Bellissimo, Catherine A.;Gandhi, Shivam;DiBenedetto, Sara N.;Garibotti, Madison C.;Thuhan, Arshdeep K.;Tsitkanou, Stavroula;Rosa-Caldwell, Megan E.;Rahman, Fasih A.;Cheng, Arthur J.;Wiggs, Michael P.;Schlattner, Uwe;Quadrilatero, Joe;Greene, Nicholas P.;Perry, Christopher G. R.
肌肉无力和萎缩是癌症引起的恶病质的典型特征。线粒体应激发生在某些肌肉萎缩之前，但肌肉之间和随时间变化的异质反应的可能性仍不清楚。使用接种了 Colon-26 癌症的小鼠，我们证明在没有萎缩的情况下，股四头肌和膈肌在 2 周时产生的比力减少。此时，股四头肌中丙酮酸支持的线粒体呼吸较低，而膈肌中线粒体 H2O2 排放量升高。到 4 周时，两块肌肉都出现萎缩，但股四头肌的特定力量产生增加到控制水平，因此绝对力量的减少完全是由于萎缩所致。隔膜中的比力产生仍然减少。与对照组相比，两种肌肉的线粒体呼吸增加，H2O2 排放量没有变化，而股四头肌的线粒体肌酸敏感性降低。这些发现表明肌肉无力先于萎缩，并与异质线粒体改变有关，可能涉及对代谢应激的适应性反应。最终在特定力和生物能学方面的肌肉特异性恢复突显了癌症对一块肌肉的影响如何无法预测另一块肌肉的反应。探索肌肉对癌症的异质反应可能会揭示对癌症恶病质的不同敏感性或抵抗力的新机制。
Muscle weakness and wasting are defining features of cancer-induced cachexia. Mitochondrial stress occurs before atrophy in certain muscles, but the possibility of heterogeneous responses between muscles and across time remains unclear. Using mice inoculated with Colon-26 cancer, we demonstrate that specific force production was reduced in quadriceps and diaphragm at 2 weeks in the absence of atrophy. At this time, pyruvate-supported mitochondrial respiration was lower in quadriceps while mitochondrial H2O2 emission was elevated in diaphragm. By 4 weeks, atrophy occurred in both muscles, but specific force production increased to control levels in quadriceps such that reductions in absolute force were due entirely to atrophy. Specific force production remained reduced in diaphragm. Mitochondrial respiration increased and H2O2 emission was unchanged in both muscles versus control while mitochondrial creatine sensitivity was reduced in quadriceps. These findings indicate muscle weakness precedes atrophy and is linked to heterogeneous mitochondrial alterations that could involve adaptive responses to metabolic stress. Eventual muscle-specific restorations in specific force and bioenergetics highlight how the effects of cancer on one muscle do not predict the response in another muscle. Exploring heterogeneous responses of muscle to cancer may reveal new mechanisms underlying distinct sensitivities, or resistance, to cancer cachexia.
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DOI：
10.1002/jcsm.12232
发表时间：
2017-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Brown JL;Rosa-Caldwell ME;Lee DE;Blackwell TA;Brown LA;Perry RA;Haynie WS;Hardee JP;Carson JA;Wiggs MP;Washington TA;Greene NP
通讯作者：
Greene NP
影响因子：
3.7
作者：
Bloemberg D;Quadrilatero J
通讯作者：
Quadrilatero J
影响因子：
3.1
作者：
Fajardo VA;Smith IC;Bombardier E;Chambers PJ;Quadrilatero J;Tupling AR
通讯作者：
Tupling AR
影响因子：
5.2
作者：
Ballarò R;Lopalco P;Audrito V;Beltrà M;Pin F;Angelini R;Costelli P;Corcelli A;Bonetto A;Szeto HH;O'Connell TM;Penna F
通讯作者：
Penna F
影响因子：
6.6
作者：
Houde VP;Donzelli S;Sacconi A;Galic S;Hammill JA;Bramson JL;Foster RA;Tsakiridis T;Kemp BE;Grasso G;Blandino G;Muti P;Steinberg GR
通讯作者：
Steinberg GR