Functional and structural characterization of anti-β1-adrenoceptor autoantibodies of spontaneously hypertensive rats

Eighteen month old spontaneously hypertensive rats (SHR-rats) showed myocardial dysfunction and autoantibodies directed against the ₁-adrenoceptor similarly as known in human dilated cardiomyopathy or Chagas' disease. The agonist-like antibodies were able to activate the ₁-adrenoceptor mediated signal transduction cascade in cultured rat cardiomyocytes and induced a long-lasting stimulatory effect resulting in a harmful adrenergic overdrive. The antibodies recognized an epitope of the second extracellular loop of the ₁-adrenoceptor identical to that epitope identified in Chagas' disease. In conclusion, our assumption is supported that old SHR-rat are an useful animal model for investigating the role of anti-₁-adrenoceptor antibodies in the induction of human cardiomyopathy.     

Expression of α1-adrenergic receptor subtypes in heart cell culture

Three ₁AR subtypes have been cloned so far and are designated as _1a, _1b, and _1d. Organspecific distribution pattern and subtype-specific effects are known but not fully understood. To address a cell-type specific expression pattern in the heart we investigated expression pattern of ₁AR subtypes on RNA and proteinlevel in heart tissue, cultured cardiomyocytes and nonmyocytes of the rat. Each ₁ARsubtype mRNA was present in neonatal and adult rat heart culture but the relative distribution pattern was significantly different. While the _1aAR subtype is preferentially expressed in adult cardiomyocytes, the _1bAR subtype was preferentially expressed in the nonmyocyte cell fraction. The RTPCR results were confirmed by Westernblotting (_1b) and immunocytochemical studies. Incubation with an ₁agonist (phenylephrine) for 72 h led to a significant reduction of the _1bAR in neonatal heart cell culture on both mRNA and protein level. In contrast, incubation with an ₁antagonist (prazosin) induced a 1.6 fold upregulation of the _1aAR mRNA without significant effects on radioligand binding and functional assay. The results indicate a distribution pattern of the ₁AR subtype which is specific for cell type and ontogeny of the rat heart and may be regulated by adrenergic agents.     

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

The age‐related impairment in muscle function results in a drastic decline in motor coordination and mobility in elderly individuals. Regular physical activity is the only efficient intervention to prevent and treat this age‐associated degeneration. However, the mechanisms that underlie the therapeutic effect of exercise in this context remain unclear. We assessed whether endurance exercise training in old age is sufficient to affect muscle and motor function. Moreover, as muscle peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) is a key regulatory hub in endurance exercise adaptation with decreased expression in old muscle, we studied the involvement of PGC‐1α in the therapeutic effect of exercise in aging. Intriguingly, PGC‐1α muscle‐specific knockout and overexpression, respectively, precipitated and alleviated specific aspects of aging‐related deterioration of muscle function in old mice, while other muscle dysfunctions remained unchanged upon PGC‐1α modulation. Surprisingly, we discovered that muscle PGC‐1α was not only involved in improving muscle endurance and mitochondrial remodeling, but also phenocopied endurance exercise training in advanced age by contributing to maintaining balance and motor coordination in old animals. Our data therefore suggest that the benefits of exercise, even when performed at old age, extend beyond skeletal muscle and are at least in part mediated by PGC‐1α.     

Peroxisome proliferator‐activated receptor γ coactivator 1α regulates mitochondrial calcium homeostasis,sarcoplasmic reticulum stress,and cell death to mitigate skeletal muscle aging

Age‐related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC‐1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen‐related receptor α‐dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC‐1α. As a result, PGC‐1α prevents tubular aggregate formation and cell death pathway activation in old muscle. Similarly, the pro‐apoptotic effects of ceramide and thapsigargin were blunted by PGC‐1α in muscle cells. Accordingly, mice with muscle‐specific gain‐of‐function and loss‐of‐function of PGC‐1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC‐1α on muscle function and overall health span in aging.     

Curcumin‐galactomannosides mitigate alcohol‐induced liver damage by inhibiting oxidative stress,hepatic inflammation,and enhance bioavailability on TLR4/MMP events compared to curcumin

Alcoholic liver diseases are classified as one of the major reasons for worldwide morbidity and mortality. Curcuminoids exhibit a wide range of pharmacological activities that are beneficial for health, including hepatoprotective effects, but its clinical significance is limited due to poor oral bioavailability. In the present study, a novel formulation of curcumin as curcumin‐galactomannosides (CGM) with enhanced oral bioavailability alleviated alcohol‐induced liver damage in wistar rats with an increased potency compared to the unformulated natural curcuminoids (CM). Ethanol administration significantly elevated liver toxicity markers, lipid peroxidation and inflammatory markers with a simultaneous reduction in antioxidant defenses. Supplementation of CGM reversed all of the pathological effects of alcohol administration, almost close to the normal level, when compared with CM. Histopathology of liver tissue also confirmed the better protective effect of CGM, indicating the enhancement in antioxidant and anti‐inflammatory effects as a function of bioavailability.