A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8.

Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation "circuity" that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.

Reliability of the heart rate variability threshold during treadmill exercise.

The heart rate variability threshold (HRVT) is a clinical parameter used to gain insight into autonomic balance. Prior validation of the HRVT has been with cycle ergometry, with no studies examining the viability of treadmill exercise. The purpose of this study was to examine the reliability of the HRVT during treadmill exercise, and to compare the HRVT to the ventilatory threshold (VT). Ten healthy, college-aged males completed two maximal graded exercise tests on a treadmill. A Polar RS800CX watch was used for heart rate and HRVT data. The HRVT was determined from three HRV variables including the root mean square of successive differences of continuous R-R intervals (RMSSD), the standard deviation of normal R-R intervals (SDNN) and the standard deviation of instantaneous beat intervals (SD1). A metabolic cart was utilized to determine the VT. Results showed no difference between the HRVT (2.4 ± 0.6 and 2.2 ± 0.3 for RMSSD, 2.8 ± 0.5 and 2.7 ± 0.5 for SDNN and 2.4 ± 0.6 and 2.3 ± 0.6 for SD1) or the VT (3.0 ± 0.3 and 3.1 ± 0.3) between trials. When compared to the VT, averaged HRVT values for RMSSD (2.3 ± 0.3) and SD1 (2.3 ± 0.5) were lower than averaged VT (2.8 ± 0.4, p < 0.05). The averaged HRVT from SDNN (2.8 ± 0.5) did not differ from the VT. These results suggest that treadmill is a viable mode for HRVT determination, and that HRVT determined by SDNN may be a better comparison to the VT.

Trpm1: Novel function at the intersection of light and pain response in the iris.

In mammals, the retina is the photosensitive tissue that is responsible for the capture of light and the transduction of the light-initiated signals to the brain. These visual signals help to drive image and non-image forming behaviors. The pupillary light reflex (PLR) is an involuntary non-image forming behavior which involves the constriction of the iris muscle tissue in response to ambient light intensity. A subset of photosensitive retinal ganglion cells provides the principal pathway for all light input to the olivary pretectal nucleus which directs the neuronal input to drive iris constriction. Transient receptor potential melastatin 1 (Trpm1) knockout mice have a severe defect in PLR, but it remains unclear how the Trpm1 channel contributes to this behavior. We have demonstrated that the reduced PLR in Trpm1-/- mice at scotopic and photopic intensities is due to a functional loss of Trpm1 in the retina as well as the iris sphincter muscle. We have also tested constriction in isolated eyes and have shown that light-driven constriction independent of signaling from the brain also requires Trpm1 expression. In both the in vivo PLR and the iris photomechanical response, melanopsin is required for the light-dependent activation. Finally, pharmacological experiments using capsaicin to activate pain afferents in the eye demonstrate that Trpm1 expression is required for all sensory driven iris constriction. Our results demonstrate for the first time that Trpm1 has a novel and necessary role in iridial cells and is required for all sensory-driven constriction in the iris.