Prenatal mechanistic target of rapamycin complex 1 (mTORC1) inhibition by rapamycin treatment of pregnant mice causes intrauterine growth restriction and alters postnatal cardiac growth, morphology, and function

BACKGROUND: Fetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of mTORC1 in intrauterine growth restriction and prenatal heart growth. METHODS AND RESULTS: We inhibited mTORC1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces mTORC1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin-treated neonates exhibit a 16% reduction in body weight compared with vehicle-treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin- versus vehicle-treated mice at birth. Although proliferation rates in neonatal rapamycin-treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle-treated neonates. Rapamycin-treated mice exhibit postnatal catch-up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal mTORC1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling. CONCLUSIONS: Prenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of mTORC1 in perinatal cardiac growth

Dietary protein restriction throughout intrauterine and postnatal life results in potentially beneficial myocardial tissue remodeling in the adult mouse heart

Diet composition impacts metabolic and cardiovascular health with high caloric diets contributing to obesity related disorders. Dietary interventions such as caloric restriction exert beneficial effects in the cardiovascular system, but alteration of which specific nutrient is responsible is less clear. This study investigates the effects of a low protein diet (LPD) on morphology, tissue composition and function of the neonatal and adult mouse heart. Mice were subjected to LPD (8.8% protein) or standard protein diet (SPD, 22% protein) throughout intrauterine and postnatal life. At birth LPD female but not male offspring exhibit reduced body weight whereas heart weight was unchanged in both sexes. Cardiomyocyte cross sectional area was increased in newborn LPD females compared to SPD, whereas proliferation, cellular tissue composition and vascularization were unaffected. Adult female mice on LPD exhibit reduced body weight but normal heart weight compared to SPD controls. Echocardiography revealed normal left ventricular contractility in LPD animals. Histology showed reduced interstitial fibrosis, lower cardiomyocyte volume and elevated numbers of cardiomyocyte and non-myocyte nuclei per tissue area in adult LPD versus SPD myocardium. Furthermore, capillary density was increased in LPD hearts. In conclusion, pre- and postnatal dietary protein restriction in mice causes a potentially beneficial myocardial remodeling

Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3

Myofibrillary myopathies (MFM) are hereditary myopathies histologically characterized by degeneration of myofibrils and aggregation of proteins in striated muscle. Cardiomyopathy is common in MFM but the pathophysiological mechanisms are not well understood. The BAG3-Pro209Leu mutation is associated with early onset MFM and severe restrictive cardiomyopathy (RCM), often necessitating heart transplantation during childhood. We report on a young male patient with a BAG3-Pro209Leu mutation who underwent heart transplantation at eight years of age. Detailed morphological analyses of the explanted heart tissue showed intracytoplasmic inclusions, aggregation of BAG3 and desmin, disintegration of myofibers and Z-disk alterations. The presence of undegraded autophagosomes, seen by electron microscopy, as well as increased levels of p62, LC3-I and WIPI1, detected by immunohistochemistry and western blot analyses, indicated a dysregulation of autophagy. Parkin and PINK1, proteins involved in mitophagy, were slightly increased whereas mitochondrial OXPHOS activities were not altered. These findings indicate that altered autophagy plays a role in the pathogenesis and rapid progression of RCM in MFM caused by the BAG3-Pro209Leu mutation, which could have implications for future therapeutic strategies

Electron Microscopy Of Wood Of Callixylon And Cordaites

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141638/1/ajb210693.pd

Development of robotic volumetric PIV: with applications in sports aerodynamics

Particle image velocimetry (PIV) is the state of the art for quantitative, full-field, 3D flow diagnostics. Despite the maturity of the technique, two bottlenecks are identified which are addressed in this thesis: the achievable measurement volume size, and the optical access to geometrically complex objects. Both aspects are well illustrated when considering the human body in sports action. Characterising the aerodynamic flow topology around an athlete demands measurement volumes on the cubic-meter scale, whereas the simultaneous illumination and imaging of the flow near the athlete’s body is challenged by the geometric complexity of the human body and the sports equipment. Focusing on sport performance, especially in timed disciplines, it is recognized that due to the shape of the human body, the aerodynamic resistance is often dominated by pressure drag. Therefore, a third element addressed in this thesis is the PIV-based pressure evaluation in the flow and on an object surface. To overcome the identified measurement constraints, a PIV system for the 3D diagnostics of large-scale and low-speed flows has been developed, synthesizing advancements in PIV imaging and illumination hardware, automation technology, tracer particle generation, and particle tracking algorithms. The so called robotic volumetric PIV concept is proposed in Part I of this thesis, along with dedicated data analysis methods to retrieve the shape of the test object, the total pressure in the fluid flow, and the aerodynamic pressure on the object surface. Part II features applications of the proposed tools in the context of sport aerodynamics, with specific examples in cycling and swimming.Aerodynamic