Korean J Physiol Pharmacol.  2025 Mar;29(2):235-244. 10.4196/kjpp.24.246.

Protective effect of maltol on pathological response of cardiomyocyte in dystrophic mice

• Lee A
• Kwon H
• Kim S
• Jeong Y
• Choi BT
• Kho C

• KMID: 2565435
• DOI: http://doi.org/10.4196/kjpp.24.246

Abstract

Heart diseases are a significant contributor to global morbidity and mortality, and despite their diverse and complex mechanisms, treatment options remain limited. Maltol, a natural compound with antioxidant and anti-inflammatory activities, exhibits potential for addressing this need. This study evaluates the cardioprotective effects of maltol in isoproterenol (ISO)-induced cardiac stress models and Duchenne muscular dystrophy (DMD). Maltol’s cardiac cytotoxicity was assessed in rodent (H9c2) and human (AC16) cells and compared with that of dapagliflozin to illustrate its cardiac safety. In ISO-induced stress models, maltol significantly reduced hypertrophic markers and inflammation while enhancing autophagy and antioxidant pathways. In the mdx mice, a DMD model, maltol treatment improved cardiac contractility and reduced pathogenic remodeling. Enhanced phosphorylation of phospholamban and trends toward higher SERCA2a expression indicated enhanced Ca 2+ handling, which is crucial in DMD cardiomyopathy. This study demonstrated that maltol has the potential to provide therapeutic benefits for DMD and other cardiac conditions characterized by hypertrophy and inflammation, as evidenced by its well-known antioxidant properties, low cytotoxicity, and capacity to enhance cardiac function and Ca 2+ handling.

Keyword

Calcium; Cardiomyocyte; Duchenne muscular dystrophy; Heart; Maltol

Figure

• 

  Fig. 1 Maltol exhibits low cardiac cytotoxicity and mitigates ISO-induced stress in cardiomyocytes. Viability of H9c2 and AC16 cells treated with various concentrations of maltol for 24 h. (A) Information of maltol. (B) Comparison of cell viability between maltol and dapagliflozin treatments in H9c2 cells. (C) Comparison of cell viability between maltol and dapagliflozin treatments in AC16 cells. (D) mRNA expression levels of NPPA, NPPB, and MYH7 in ISO-treated H9c2 cells with and without maltol treatment. (E) Protein levels of BNP in ISO-treated H9c2 cells with and without maltol treatment. (F) Changes in the surface area of ISO-induced AC16 cardiomyocytes with and without maltol treatment. The cell size was measured by immunofluorescence staining with alpha-actinin, using DAPI for nuclear staining, and images were captured at 40× magnification. (G) mRNA expression levels of IL1B, IL10, LC3, SIRT1, and HO1 in ISO-treated AC16 cells with and without maltol treatment. Data are means ± SD. ISO, isoproterenol; MAL, maltol; DAPA, dapagliflozin; NT, no treatment. *p < 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.

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  Fig. 2 Maltol treatment improves cardiac function in mdx mice with Duchenne muscular dystrophy. (A) Experimental design and treatment regimen for mdx and WT mice with maltol. (B) Body weight (BW) changes in WT and mdx mice treated with vehicle or maltol. (C) Representative M-mode echocardiography images of WT and mdx mice. Quantitative analysis of (D) systolic left ventricular internal diameter (LVIDs), (E) fractional shortening (FS), (F) ejection fraction (EF), (G) left ventricular posterior wall thickness (LVPWd), (H) interventricular septal thickness (IVSd), (I) heart rate (HR) in WT and mdx mice treated with vehicle or maltol. Each dot represents an individual animal. Data are means ± SD. PO, per os; WT, wild-type; VEH, vehicle; MAL, maltol; ns, not significant. *p < 0.05.

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  Fig. 3 Maltol treatment enhances phospholamban (PLN) phosphorylation and modulates Ca2+ handling signaling proteins in mdx hearts. (A) Representative immunoblots showing phosphorylation levels of PLN and PLN in WT and mdx mice hearts treated with vehicle or maltol. GAPDH was used as a loading control. (B) Quantitative analysis of phosphorylated PLN and total PLN in WT and mdx mice hearts. (C) Immunoblots showing expression levels of SERCA2a and NCX1 in WT and mdx mice hearts treated with vehicle or maltol. (D) Quantitative analysis of SERCA2a and NCX1 in WT and mdx mice hearts treated with vehicle or maltol. Data are means ± SD. WT, wild-type; VEH, vehicle; MAL, maltol; ns, not significant. *p < 0.05.

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  Fig. 4 Maltol treatment attenuates the upregulation of fibrosis and inflammatory genes in mdx mouse hearts. mRNA expression levels of (A) COL1A1, (B) POSTN, and (C) IL1B in wild-type (WT) and mdx mouse hearts treated with vehicle (MDX + VEH) or 50 mpk maltol (MDX + MAL 50 mpk), as determined by qPCR analysis. Data represent 3 to 5 animals per group and are presented as means ± SD. *p < 0.05; **p ≤ 0.01; ***p ≤ 0.001.

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