Sodium nitrate co-supplementation does not exacerbate low dose metronomic doxorubicin-induced cachexia in healthy mice

Abstract

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.

The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction

“…Echo magnetic resonance imaging (echoMRI) was utilized to assess the effect of IRI treatment and BGP-15 adjuvant therapy on body composition indices of lean and fat mass. Live mice were placed into an echoMRI body composition analyzer (EMR-150, Echo Medical Systems, Houston, TX, USA) on day 1 (Pre) and day 15 (Post) of the treatment protocol, as previously described [ 8 ]. Lean and fat mass was quantified via triplicate scans spaced 30 s apart and reported as the mean of these triplicate scans.…”

“…Cages allowed free access to food, water and a running wheel. Real-time voluntary activity associated with wheel running and general cage-based ambulatory activity was evaluated as described by us previously [ 8 , 36 ]. Data presented pertain to the total 24-h post-treatment period.…”

“…It is a complex wasting syndrome defined as a >5% loss of body mass, which features lean tissue wasting with or without a loss of fat mass [ 1 ], as well as prominent skeletal myopathy that manifests as both wasting and dysfunction [ 2 , 3 , 4 ]. Historically, cancer-related cachexia was considered a tumor-induced phenomenon; however, mounting evidence suggests that chemotherapy drugs plays a prominent role in the progression of cachexia independent of the tumor [ 5 , 6 , 7 , 8 ]. Several chemotherapeutic agents from different drug classes (and with different mechanisms of action) elicit skeletal muscle toxicity [ 9 ], which, at the molecular level, involves disruption of proteostasis in favor of protein degradation and mitochondrial dysfunction through which oxidative stress/damage is escalated [ 10 , 11 , 12 ].…”

Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle for Myopathy but Does Not Cause Cachexia

“…p38 and NF-κB phosphorylation) that are usually associated with the induction of chemotherapy-induced cachexia and skeletal myopathy [11,15]. The lack of change to these physiological parameters from 5FU treatment may be due to the metronomic delivery of chemotherapy, which typically elicits less systemic toxicity than administration of single maximum tolerable dose (MTD) bolus or sequential daily treatments [32,55]. Metronomic delivery could activate an adaptive hormetic response which prevents the induction of skeletal myopathy in the face of low-grade stress signalling.…”

“…Echo Magnetic Resonance Imaging (echoMRI) was utilized to assess the effect of 5FU treatment and BGP-15 co-therapy on body composition indices of lean and fat mass. Live mice were placed into an echoMRI body composition analyzer (EMR-150, Echo Medical Systems, USA) on day 1 (Pre) and day 15 (Post) of the treatment protocol, as previously described [32]. Lean and fat mass was quantified via triplicate scans spaced 30 seconds apart and reported as the mean of these triplicate scans.…”