Wang Ruizhong, Kumar Brijesh, Doud Emma H, Mosley Amber L, Alexander Matthew S, Kunkel Louis M, Nakshatri Harikrishna
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Mol Ther Nucleic Acids. 2022 Mar 16;28:231-248. doi: 10.1016/j.omtn.2022.03.009. eCollection 2022 Jun 14.
miR-486 is a myogenic microRNA, and its reduced skeletal muscle expression is observed in muscular dystrophy. Transgenic overexpression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues muscular dystrophy phenotype. We had previously demonstrated reduced circulating and skeletal muscle miR-486 levels with accompanying skeletal muscle defects in mammary tumor models. To determine whether skeletal muscle miR-486 is functionally similar in dystrophies and cancer, we performed functional limitations and biochemical studies of skeletal muscles of MMTV-Neu mice that mimic HER2+ breast cancer and MMTV-PyMT mice that mimic luminal subtype B breast cancer and these mice crossed to MCK-miR-486 mice. miR-486 significantly prevented tumor-induced reduction in muscle contraction force, grip strength, and rotarod performance in MMTV-Neu mice. In this model, miR-486 reversed cancer-induced skeletal muscle changes, including loss of p53, phospho-AKT, and phospho-laminin alpha 2 (LAMA2) and gain of hnRNPA0 and SRSF10 phosphorylation. LAMA2 is a part of the dystrophin-associated glycoprotein complex, and its loss of function causes congenital muscular dystrophy. Complementing these beneficial effects on muscle, miR-486 indirectly reduced tumor growth and improved survival, which is likely due to systemic effects of miR-486 on production of pro-inflammatory cytokines such as IL-6. Thus, similar to dystrophy, miR-486 has the potential to reverse skeletal muscle defects and cancer burden.
miR-486是一种成肌微小RNA，在肌肉营养不良症中可观察到其在骨骼肌中的表达降低。使用肌肉肌酸激酶启动子（MCK-miR-486）对miR-486进行转基因过表达可部分挽救肌肉营养不良症的表型。我们之前已经证明，在乳腺肿瘤模型中，循环和骨骼肌中的miR-486水平降低，并伴有骨骼肌缺陷。为了确定骨骼肌miR-486在营养不良症和癌症中是否具有相似的功能，我们对模拟HER2+乳腺癌的MMTV-Neu小鼠和模拟B型管腔亚型乳腺癌的MMTV-PyMT小鼠以及与MCK-miR-486小鼠杂交的这些小鼠的骨骼肌进行了功能限制和生化研究。miR-486显著预防了MMTV-Neu小鼠中肿瘤诱导的肌肉收缩力、握力和转棒性能的降低。在该模型中，可以看到miR-486逆转了癌症诱导的骨骼肌变化，包括p53、磷酸化AKT和磷酸化层粘连蛋白α2（LAMA2）的缺失以及hnRNPA0和SRSF10磷酸化的增加。LAMA2是抗肌萎缩蛋白相关糖蛋白复合物的一部分，其功能丧失会导致先天性肌肉营养不良。作为对肌肉的这些有益作用的补充，miR-486间接减少了肿瘤生长并提高了存活率，这可能是由于miR-486对促炎细胞因子如IL-6产生的全身作用。因此，与营养不良症类似，miR-486有可能逆转骨骼肌缺陷和癌症负担。
