Abstract
Doxorubicin (DOX) remains a cornerstone of cancer treatment but is limited by its dose-dependent cardiotoxicity, and clinical care for cancer survivors has not yet overcome the poor prognosis of DOX-induced heart failure (HF). PURPOSE: To identify early events that are associated with HF development in rats treated with DOX. METHODS: 42 Male Wistar rats received either DOX (4 weekly I.P. injections of 2.5mg/Kg; D, n=24) or equal volume of saline solution (C, n=18). Rats were evaluated after DOX treatment – baseline timepoint (CB or DB) and following 6 weeks of recovery – final timepoint (CF or DF). RESULTS: No animals died during DOX treatment; however, mortality during recovery was 33.33% in the DOX group (6 rats). Cardiac injury was assessed by plasma concentrations of the biomarker NT-proBNP and did not differ between groups at baseline timepoint but was significantly elevated at the recovery timepoint in DF group compared to CF (CB: 334±96.7, CF: 334±89.5, DB: 405±123, DF:607±166 pg/mL, p<0.05). Similarly, exercise tolerance, assessed on a treadmill test by total time until fatigue, declined only after recovery (CB: 23.82±2.87, DB: 22.75±3.13, CF: 24.16±2.27, DF: 19.42±2.79 min, p<0.05). Regarding body composition, the percentage lean mass was not significantly different at either time point. The percentage body fat was significantly lower after DOX treatment and did not rebound after 6 weeks of recovery from DOX (CB: 8.96±0.308; DB: 4.22±2.12; CF: 12.33±4.17; DF: 4.18±2.13 %, p<0.05), correlating inversely with plasma NT-proBNP (Pearson’s r = –0.5217, p=0.02). Reductions in adipose tissue (AT) mass could be due to dysregulation of AT metabolism; therefore, we measured systemic markers of AT function — triglycerides and adiponectin — in plasma. Adiponectin was significantly reduced at the final time point compared to the control counterpart, but there were no differences at baseline (CB: 3.05±0.48; DB: 2.61±0.68; CF: 4.23±0.86; DF: 2.49±0.67 ug/mL, p<0.05). Triglycerides were not significantly different (CB: 42.5±13.2; DB: 57.5±8.7; CF: 46.8±9.1; DF: 165.6±134.2 mg/dL, p>0.05). We then evaluated AT gene expression related to lipid metabolism by RT-qPCR. AMP-activated protein kinase (Prkaa2) expression and its downstream targets, lipoprotein lipase (Lpl) and patatin like domain 2 (Pnpla2), were significantly reduced in DOX groups compared to their counterparts at both timepoints (Prkaa2, CB: 1.04±0.33, DB: 0.74±0.26, CF: 1.01±.015, DF: 0.64±0.29 A.U. relative to C p<0.05; Lpl, CB: 1.05±0.38, DB: 0.61±0.29, CF: 1.01±0.14, DF: 0.46±0.35 A.U. relative to C, p<0.05; Pnpla2, CB: 1.01±0.19, DB: 0.56±0.34, CF: 1.01±0.12, DF: 0.47±0.41 A.U. relative to C, p<0.05). CONCLUSION: DOX induces persistent AT transcriptional changes that do not rebound following recovery from treatment. The onset of AT dysregulation may precede cardiac injury and contribute to HF and late mortality following DOX treatment. AMPK is a key sensor regulating lipid metabolism; these data suggest that strategies aimed at preserving or restoring AT function via enhancing AMPK signaling may represent a promising approach to mitigate DOX-induced cardiotoxicity.
Recommended Citation
Pigg, Quinten W.; Harris, Dillon; Sayuri Inoue, Daniela; and Janini Gomes, Mariana
(2026)
"Adipose Tissue Dysfunction as a Novel Contributor to Heart Failure Following Recovery from Doxorubicin Treatment,"
International Journal of Exercise Science: Conference Proceedings: Vol. 2:
Iss.
18, Article 106.
Available at:
https://digitalcommons.wku.edu/ijesab/vol2/iss18/106