Aging-associated skeletal muscle defects in HER2/Neu transgenic mammary tumor model.
Aging-associated skeletal muscle defects in HER2/Neu transgenic mammary tumor model.
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DOI：
10.1002/rco2.23
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发表时间：
2021-01
影响因子：
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通讯作者：
Nakshatri H
中科院分区：
文献类型：
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作者：
Wang R;Kumar B;Bhat-Nakshatri P;Prasad MS;Jacobsen MH;Ovalle G;Maguire C;Sandusky G;Trivedi T;Mohammad KS;Guise T;Penthala NR;Crooks PA;Liu J;Zimmers T;Nakshatri H
骨骼肌体积的损失和导致的功能限制是乳腺癌患者预后不良的标志。骨骼肌中的几种分子缺陷，包括MyoD水平降低和蛋白质周转增加（由于蛋白酶体活性增强），已被认为是癌症患者骨骼肌损失的原因。然而，目前尚不清楚骨骼肌中的分子缺陷是否取决于肿瘤病因。我们表征了MMTV-Neu（Neu+）小鼠（n= 6-12）（代表HER 2+人乳腺癌的动物模型）中骨骼肌的功能和分子缺陷，并将结果与充分表征的管腔B乳腺癌模型MMTV-PyMT（PyMT+）进行了比较。进行了握力、转棒性能和离体肌肉收缩等功能研究，以测量癌症对骨骼肌的影响。测量肌肉富集基因和microRNA以及循环细胞因子/趋化因子的表达。由于NF-κB途径在骨骼肌缺陷中起重要作用，因此检测了NF-κB抑制剂二甲基氨基蝶呤（DMAPT）逆转骨骼肌缺陷的能力。Neu+小鼠表现出与加速老化相似的骨骼肌缺陷。与年龄和性别匹配的野生型小鼠相比，荷Neu+肿瘤的小鼠具有较低的握力（202±6.9对179±6.8 g握力，p=0.0069）和受损的转棒性能（108±12.1对30±3.9秒，P<0.0001），这与降低的肌肉收缩性一致（p<0.0001）。Neu+小鼠（n=6）的骨骼肌含有较低水平的CD 82+（16.2±2.9 vs 9.0±1.6）和CD 54+（3.8±0.5 vs 2.4±0.4）肌肉干细胞和祖细胞（p<0.05），表明肌肉再生能力受损，这伴随着肌肉中MyoD、p53和miR-486表达降低（p<0.05）。与PyMT+小鼠不同，PyMT+小鼠表现出骨骼肌线粒体缺陷，包括线粒体水平和Pgc 1 β降低，Neu+小鼠表现出加速的衰老相关变化，包括肌纤维收缩和细胞外基质沉积增加。循环“衰老因子”和恶病质以及纤维肌痛相关趋化因子Ccl 11在Neu+小鼠中升高（1439.56±514 vs. 1950±345 pg/ml，p<0.05）。用DMAPT治疗Neu+小鼠显著恢复了握力（205±6 g力）、转棒性能（74±8.5秒）、逆转了与骨骼肌老化相关的分子改变、降低了循环Ccl 11（1083.26 ±478 pg/ml）并改善了动物存活率。这些结果表明，乳腺癌亚型对骨骼肌的分子和结构变化类型有特定的影响，在设计治疗方法以减少乳腺癌引起的骨骼肌损失和功能限制时需要考虑到这一点。
Loss of skeletal muscle volume and resulting in functional limitations are poor prognostic markers in breast cancer patients. Several molecular defects in skeletal muscle including reduced MyoD levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumor etiology. We characterized functional and molecular defects of skeletal muscle in MMTV-Neu (Neu+) mice (n= 6–12), an animal model that represents HER2+ human breast cancer, and compared the results with well-characterized luminal B breast cancer model MMTV-PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and ex vivo muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle-enriched genes and microRNAs as well as circulating cytokines/chemokines were measured. Since NF-κB pathway plays a significant role in skeletal muscle defects, the ability of NF-κB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined. Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared to age and sex-matched wild type mice, Neu+ tumor-bearing mice had lower grip strength (202±6.9 vs. 179±6.8 g grip force, p=0.0069) and impaired rotarod performance (108±12.1 vs. 30±3.9 seconds, P<0.0001), which was consistent with reduced muscle contractibility (p<0.0001). Skeletal muscle of Neu+ mice (n=6) contained lower levels of CD82+ (16.2±2.9 vs 9.0±1.6) and CD54+ (3.8±0.5 vs 2.4±0.4) muscle stem and progenitor cells (p<0.05), suggesting impaired capacity of muscle regeneration, which was accompanied by decreased MyoD, p53 and miR-486 expression in muscles (p<0.05). Unlike PyMT+ mice, which showed skeletal muscle mitochondrial defects including reduced mitochondria levels and Pgc1β, Neu+ mice displayed accelerated aging-associated changes including muscle fiber shrinkage and increased extracellular matrix deposition. Circulating “aging factor” and cachexia and fibromyalgia-associated chemokine Ccl11 was elevated in Neu+ mice (1439.56±514 vs. 1950±345 pg/ml, p<0.05). Treatment of Neu+ mice with DMAPT significantly restored grip strength (205±6 g force), rotarod performance (74±8.5 seconds), reversed molecular alterations associated with skeletal muscle aging, reduced circulating Ccl11 (1083.26 ±478 pg/ml), and improved animal survival. These results suggest that breast cancer subtype has a specific impact on the type of molecular and structure changes in skeletal muscle, which needs to be taken into consideration while designing therapies to reduce breast cancer-induced skeletal muscle loss and functional limitations.