Matrix-guided control of mitochondrial function in cardiac myocytes

• Published in: Acta biomaterialia Vol. 97; pp. 281 - 295
• Main Authors: Lyra-Leite, Davi M., Andres, Allen M., Cho, Nathan, Petersen, Andrew P., Ariyasinghe, Nethika R., Kim, Suyon Sarah, Gottlieb, Roberta A., McCain, Megan L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2019; Elsevier BV
• Subjects: Acidification; Animals; Biocompatibility; Biomaterials; Biomedical materials; Cardiac muscle; Cardiomyocytes; Cell morphology; Coated Materials, Biocompatible - chemistry; Cytology; Cytotoxicity; Extracellular flux analyzer; Extracellular matrix; Extracellular Matrix Proteins - chemistry; Fibronectin; Gelatin; Glycolysis; Heart; Hydrogels; Hydrogels - chemistry; Mechanical properties; Mechanotransduction; Metabolic response; Metabolism; Mice; Mitochondria, Heart - metabolism; Mitochondrial DNA; Modulus of elasticity; Morphology; Myoblasts, Cardiac - cytology; Myoblasts, Cardiac - metabolism; Myocardium; Myocytes; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Neonates; Oxygen consumption; PDMS; Polydimethylsiloxane; Rewiring; Rigidity; Silicone resins; Substrates; Toxicity; Ventricle; Mechanotransduction; Hydrogels; Metabolism; Extracellular flux analyzer; PDMS
• ISSN: 1742-7061; 1878-7568; 1878-7568
• DOI: 10.1016/j.actbio.2019.08.007

[Display omitted] In ventricular myocardium, extracellular matrix (ECM) remodeling is a hallmark of physiological and pathological growth, coincident with metabolic rewiring of cardiac myocytes. However, the direct impact of the biochemical and mechanical properties of the ECM on the metabolic function of cardiac myocytes is mostly unknown. Furthermore, understanding the impact of distinct biomaterials on cardiac myocyte metabolism is critical for engineering physiologically-relevant models of healthy and diseased myocardium. For these reasons, we systematically measured morphological and metabolic responses of neonatal rat ventricular myocytes cultured on fibronectin- or gelatin-coated polydimethylsiloxane (PDMS) of three elastic moduli and gelatin hydrogels with four elastic moduli. On all substrates, total protein content, cell morphology, and the ratio of mitochondrial DNA to nuclear DNA were preserved. Cytotoxicity was low on all substrates, although slightly higher on PDMS compared to gelatin hydrogels. We also quantified oxygen consumption rates and extracellular acidification rates using a Seahorse extracellular flux analyzer. Our data indicate that several metrics associated with baseline glycolysis and baseline and maximum mitochondrial function are enhanced when cardiac myocytes are cultured on gelatin hydrogels compared to all PDMS substrates, irrespective of substrate rigidity. These results yield new insights into how mechanical and biochemical cues provided by the ECM impact mitochondrial function in cardiac myocytes. Cardiac development and disease are associated with remodeling of the extracellular matrix coincident with metabolic rewiring of cardiac myocytes. However, little is known about the direct impact of the biochemical and mechanical properties of the extracellular matrix on the metabolic function of cardiac myocytes. In this study, oxygen consumption rates were measured in neonatal rat ventricular myocytes maintained on several commonly-used biomaterial substrates to reveal new relationships between the extracellular matrix and cardiac myocyte metabolism. Several mitochondrial parameters were enhanced on gelatin hydrogels compared to synthetic PDMS substrates. These data are important for comprehensively understanding matrix-regulation of cardiac myocyte physiology. Additionally, these data should be considered when selecting scaffolds for engineering in vitro cardiac tissue models.