Morena Francielly, Lim Seongkyun, Cabrera Ana Regina, Chambers Toby L, Koopmans Pieter J, Tsitkanou Stavroula, Khadgi Sabin, Peterson Calvin, Schrems Eleanor R, Muhyudin Ruqaiza, Shakeri Sepideh, Zhao Kevin, Mishra Devan, Washington Tyrone A, Murach Kevin A, Greene Nicholas P
Department of Health, Human Performance and Recreation, Cachexia Research Laboratory, Exercise Science Research Center, University of Arkansas, 155 Stadium Dr., Fayetteville, AR, 72701, USA.
Department of Health, Human Performance and Recreation, Molecular Muscle Mass Regulation Laboratory, Exercise Science Research Center, University of Arkansas, Fayetteville, AR, USA.
BMC Cancer. 2025 Aug 11;25(1):1300. doi: 10.1186/s12885-025-14630-x.
Skeletal muscle atrophy during cancer-induced cachexia remains a significant challenge in cancer management. Mitochondrial defects precede muscle mass and functional losses in models of cancer cachexia (CC). We hypothesized targeting Opa1-a key regulator of mitochondrial fusion-can attenuate LLC-induced CC outcomes.
We utilized 1) in vivo transgenic Opa1 overexpression (OPA1 TG) in LLC-induced CC in vivo, and 2) BPG15 administration to induce Opa1 in vitro and in vivo.
OPA1 TG attenuated plantaris, gastrocnemius, and EDL loss with LLC in males and alleviated gastrocnemius loss in females. OPA1 TG had greater mitochondrial respiration in plantaris and white gastrocnemius, and lowered pMitoTimer Red Puncta (-63%), a proxy for mitophagy in males. OPA1 TG protected muscle contractility at physiological stimulation frequencies by up to 60% in female LLC mice. OPA1 TG enhanced the ratio of OPA1/DRP1 protein content-a proxy for fusion and fission balance-in males and females. In vitro, BGP-15 attenuated LLC conditioned media-induced myotube atrophy by ~ 9% concomitant with suppression of the transcriptional factor FoxO3, autophagy markers, and inflammatory cytokines. In vivo, BGP-15 improved contractility at lower frequencies (10-60 Hz), with LLC-BGP-15 showing up to 20% greater torque than LLC-control. BGP-15 treated LLC animals had 71% fewer pMitoTimer red puncta, suggesting attenuated mitophagy.
Promoting mitochondrial fusion via OPA1 induction improved cachectic outcomes in mice. Targeting OPA1providing provides a promising therapeutic approach for CC treatment.
癌症诱导的恶病质期间骨骼肌萎缩仍然是癌症治疗中的一项重大挑战。在癌症恶病质（CC）模型中，线粒体缺陷先于肌肉质量和功能丧失出现。我们假设靶向线粒体外膜转位酶1（Opa1）——线粒体融合的关键调节因子——可以减轻LLC诱导的CC结局。
我们采用了1）在体内LLC诱导的CC模型中进行转基因Opa1过表达（OPA1 TG），以及2）给予BPG15在体内外诱导Opa1。
OPA1 TG减轻了雄性小鼠因LLC导致的比目鱼肌、腓肠肌和趾长伸肌损失，并减轻了雌性小鼠的腓肠肌损失。OPA1 TG使雄性小鼠比目鱼肌和白色腓肠肌的线粒体呼吸增强，并降低了pMitoTimer红色斑点（-63%），这是雄性小鼠线粒体自噬的一个指标。OPA1 TG在生理刺激频率下使雌性LLC小鼠的肌肉收缩力提高了60%。OPA1 TG提高了雄性和雌性小鼠OPA1/动力相关蛋白1（DRP1）蛋白含量的比值——这是融合与裂变平衡的一个指标。在体外，BGP-15使LLC条件培养基诱导的肌管萎缩减轻了约9%，同时抑制了转录因子叉头框蛋白O3（FoxO3）、自噬标志物和炎性细胞因子。在体内，BGP-15在较低频率（10 - 60Hz）下改善了收缩力，LLC - BGP-15组的扭矩比LLC -对照组高20%。经BGP-15处理的LLC动物的pMitoTimer红色斑点减少了71%，表明线粒体自噬减弱。
通过诱导Opa1促进线粒体融合可改善小鼠恶病质结局。靶向Opa1为CC治疗提供了一种有前景的治疗方法。
