Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, St Albans, Victoria, Australia.
Sci Rep. 2020 Sep 24;10(1):15044. doi: 10.1038/s41598-020-71974-z.
The purpose of this study was to determine whether (1) sodium nitrate (SN) treatment progressed or alleviated doxorubicin (DOX)-induced cachexia and muscle wasting; and (2) if a more-clinically relevant low-dose metronomic (LDM) DOX treatment regimen compared to the high dosage bolus commonly used in animal research, was sufficient to induce cachexia in mice. Six-week old male Balb/C mice (n = 16) were treated with three intraperitoneal injections of either vehicle (0.9% NaCl; VEH) or DOX (4 mg/kg) over one week. To test the hypothesis that sodium nitrate treatment could protect against DOX-induced symptomology, a group of mice (n = 8) were treated with 1 mM NaNO in drinking water during DOX (4 mg/kg) treatment (DOX + SN). Body composition indices were assessed using echoMRI scanning, whilst physical and metabolic activity were assessed via indirect calorimetry, before and after the treatment regimen. Skeletal and cardiac muscles were excised to investigate histological and molecular parameters. LDM DOX treatment induced cachexia with significant impacts on both body and lean mass, and fatigue/malaise (i.e. it reduced voluntary wheel running and energy expenditure) that was associated with oxidative/nitrostative stress sufficient to induce the molecular cytotoxic stress regulator, nuclear factor erythroid-2-related factor 2 (NRF-2). SN co-treatment afforded no therapeutic potential, nor did it promote the wasting of lean tissue. Our data re-affirm a cardioprotective effect for SN against DOX-induced collagen deposition. In our mouse model, SN protected against LDM DOX-induced cardiac fibrosis but had no effect on cachexia at the conclusion of the regimen.
（1）硝酸钠（SN）治疗是否能促进或缓解阿霉素（DOX）诱导的恶病质和肌肉消耗；（2）与动物研究中常用的高剂量冲击疗法相比，更为临床相关的低剂量节拍 DOX 治疗方案是否足以在小鼠中引起恶病质。6 周龄雄性 Balb/C 小鼠（n=16）接受 3 次腹腔注射生理盐水（0.9% NaCl；VEH）或 DOX（4mg/kg），每周 1 次。为了验证 SN 治疗可能预防 DOX 诱导的症状的假说，一组小鼠（n=8）在 DOX（4mg/kg）治疗期间饮用 1mM NaNO3 溶液（DOX+SN）。在治疗方案前后，使用 echoMRI 扫描评估身体成分指标，通过间接量热法评估身体和代谢活动。切除骨骼肌和心肌以研究组织学和分子参数。LDM DOX 治疗引起恶病质，对体重和瘦体重均有显著影响，同时疲劳/不适（即减少了自发轮跑和能量消耗），这与氧化/硝化应激有关，足以诱导分子细胞毒性应激调节剂核因子红细胞 2 相关因子 2（NRF-2）。SN 联合治疗没有治疗潜力，也没有促进瘦组织的消耗。我们的数据再次证实了 SN 对 DOX 诱导的胶原蛋白沉积具有心脏保护作用。在我们的小鼠模型中，SN 可预防 LDM DOX 诱导的心脏纤维化，但在治疗方案结束时对恶病质没有影响。
