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 NaNO₃ 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.

本研究的目的是确定 (1) 硝酸钠 (SN) 治疗是否进展或减轻了多柔比星 (DOX) 诱导的恶病质和肌肉萎缩；(2) 与动物研究中常用的高剂量推注相比，是否有更临床相关的低剂量节拍 (LDM) DOX 治疗方案，这足以诱导小鼠恶病质。6 周龄雄性 Balb/C 小鼠（n = 16）在一周内接受 3 次腹膜内注射载体（0.9% NaCl；VEH）或 DOX（4 mg/kg）治疗。为了检验硝酸钠治疗可以防止 DOX 诱导的症状的假设，一组小鼠（n = 8）用 1 mM NaNO ₃治疗在 DOX (4 mg / kg) 处理 (DOX + SN) 期间的饮用水中。在治疗方案之前和之后，使用 echoMRI 扫描评估身体成分指数，而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 治疗诱导恶病质，对身体和瘦体重都有显着影响，以及与氧化/亚硝化应激相关的疲劳/不适（即它减少了自愿车轮运行和能量消耗），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，也没有促进瘦肉组织的消耗。我们的数据再次证实了 SN 对 DOX 诱导的胶原沉积的心脏保护作用。在我们的小鼠模型中，SN 可防止 LDM DOX 诱导的心脏纤维化，但在方案结束时对恶病质没有影响。