MicroRNA‐378a Loss Enhances Mitochondrial Bioenergetics and Lessens Cardiac Contractile Dysfunction in the Type 2 Diabetic Heart

Abstract

During type 2 diabetes mellitus (T2DM), microRNA (miR) function can diverge and become pathological. Decreases in mitochondrial bioenergetic function contribute to the development of cardiovascular contractile dysfunction, making the mitochondrion and pathologically inclined miRs, a potential target for therapeutic intervention. MiR‐378a interacts with the mitochondrial genome, and during T2DM, is associated with a decrease in the mitochondrial genome‐encoded protein, ATP6. Loss of ATP6, a key component of the ATP synthase complex, results in decreased ATP synthase activity and ATP generating capacity of the electron transport chain (ETC). The objective of this study was to determine if genetic loss of miR‐378a could ameliorate the decrements in cardiac function observed in the type 2 diabetic heart, through restoration of ATP6 protein content, improved ATP generating capacity, and improved cardiac contractile dysfunction. A miRNA‐378a knockout (KO) mouse model was bred into a Db/Db background to produce miR‐378aKO/Db/Db (KO/Db/Db) mice. At 25 weeks of age, M‐mode echocardiography‐based measures (ejection fraction and fractional shortening (p < 0.05)), indicated preservation of cardiac contractile function in KO/Db/Db mice which was complemented by a reversal of long‐axis diastolic radial and longitudinal strain patterns (p < 0.05 for both). Mitochondrial oxygen consumption was evaluated in KO/Db/Db mice using glutamate/malate (GM) and palmitoylcarnitine (PM) substrates. A higher GM‐dependent respiratory control ratio (RCR) was observed in KO/Db/Db mice when compared to Db/Db mice (p < 0.05). Further, KO/Db/Db mice displayed significantly lower PM‐dependent state 3 and state 4 respiration rates when compared to Db/Db counterparts (p < 0.05), and a higher RCR in both diabetic groups when compared to wild‐type controls (p < 0.05). ETC complex activity analyses revealed increased ATP synthase activity in KO/Db/Db mice (p < 0.05), that was supported by increases in mt‐ATP6 and mt‐ATP8 protein content in KO/Db/Db mice (p < 0.05). In summary, loss of miRNA‐378a content in the type 2 diabetic heart preserved cardiac contractile function and lead to a reduced dependence on fatty acid metabolism as suggested by reduced ability to utilize PM substrate and increased GM‐dependent RCR. This data provides evidence for the efficacy of miRNA targeted mitochondrial therapeutics in a mouse model of T2DM.Support or Funding InformationThis work was supported by: The National Heart, Lung, and Blood Institute [R01 HL‐128485] (JMH), American Heart Association [AHA‐17PRE33660333] (QAH), West Virginia IDeA Network of Biomedical Research WV‐INBRE support by National Institute of Health Grant [P20GM103434], and the Community Foundation for the Ohio Valley Whipkey Trust.