Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart

Abstract

Impaired mitochondrial biogenesis causes skeletal muscle damage in diabetes. However, whether and how mitochondrial biogenesis is impaired in the diabetic heart remains largely unknown. Whether adiponectin (APN), a potent cardioprotective molecule, regulates cardiac mitochondrial function has also not been previously investigated. In this study, electron microscopy revealed significant mitochondrial disorders in ob/ob cardiomyocytes, including mitochondrial swelling and cristae disorientation and breakage. Moreover, mitochondrial biogenesis of ob/ob cardiomyocytes is significantly impaired, as evidenced by reduced Ppargc-1a/Nrf-1/Tfam mRNA levels, mitochondrial DNA content, ATP content, citrate synthase activity, complexes I/III/V activity, AMPK phosphorylation, and increased PGC-1α acetylation. Since APN is an upstream activator of AMPK and APN plasma levels are significantly reduced in ob/ob mice, we further tested the hypothesis that reduced APN in ob/ob mice is causatively related to mitochondrial biogenesis impairment. One week of APN treatment of ob/ob mice activated AMPK, reduced PGC-1α acetylation, increased mitochondrial biogenesis, and attenuated mitochondrial disorders. In contrast, knocking out APN inhibited AMPK-PGC-1α signaling and impaired both mitochondrial biogenesis and function. The ob/ob mice exhibited lower survival rates and exacerbated myocardial injury after MI, when compared to controls. APN supplementation improved mitochondrial biogenesis and attenuated MI injury, an effect that was almost completely abrogated by the AMPK inhibitor compound C. In high glucose/high fat treated neonatal rat ventricular myocytes, siRNA-mediated knockdown of PGC-1α blocked gAd-enhanced mitochondrial biogenesis and function and attenuated protection against hypoxia/reoxygenation injury. In conclusion, hypoadiponectinemia impaired AMPK-PGC-1α signaling, resulting in dysfunctional mitochondrial biogenesis that constitutes a novel mechanism for rendering diabetic hearts more vulnerable to enhanced MI injury.

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…PGC-1α can induce NRF-1 expression, which, in turn, activates Tfam to directly regulate mitochondrial biogenesis (Hickey et al 2011, Agrawal et al 2014. This association has been confirmed by the in vivo and in vitro (Yan et al 2013) results. Secondly, PGC-1α participates in insulin-stimulated glucose uptake in muscle cells by binding with the muscle-selective transcription factor MEF2C and coactivating it, thus controlling the level of GLUT4 expression (Michael et al 2001).…”

Effects of neonatal dexamethasone administration on cardiac recovery ability under ischemia-reperfusion in 24-wk-old rats

“…Metabolic defects such as hyperlipidemia and insulin resistance may impair cardiac functional recovery post-I/R by attenuating mitochondrial biogenesis (29), enhancing oxidative stress, (30) and causing intracellular Ca(2+)-overload (31). Mitochondria may also be affected by early-life factors (32).…”

“…Repressed PGC-1α expression has been noted in cardiac hypertrophy, heart failure, (35,36) and the latter stages of diabetes, in which changes in mitochondrial architecture have also been noted (37). Impaired cardiac AMPK/PGC-1α signaling caused by hypoadiponectinemia may result in reduced mitochondrial biogenesis, rendering hearts more vulnerable to ischemic injury (29). Metformin, an antidiabetes drug, may protect the heart against I/R damage by increasing the expression of phosphorylated AMPK and PGC-1α, which are associated with…”

Adiponectin downregulation is associated with volume overload-induced myocyte dysfunction in rats

“…Myocardial protein expression of AdipoR1/R2 and T-cadherin in myocytes isolated from fistula+Ad-APN rats was comparable to that in myocytes from control rats (Figure 2). APN functions to mediate myocardial glucose uptake and fatty acid oxidation as well as to provide cardioprotective roles by increased AMPK activity through phosphorylation of AMPK-α (Thr172) [24] . In this study, Western blot was used to assess the phosphorylation status of AMPK at threonine residue 172 of the α subunit in myocytes from rats in each group.…”