Comprehensive Physiology最新文献

The evolution of mechanisms for terrestrial locomotion has resulted in multi-segmented limbs that allow navigation on irregular terrains, changing of direction, manipulation of external objects, and control over the mechanical properties of limbs important for interaction with the environment, with corresponding changes in neural pathways in the spinal cord. This article is focused on the organization of these pathways, their interactions with the musculoskeletal system, and the integration of these neuromechanical circuits with supraspinal mechanisms to control limb impedance. It is argued that neural pathways from muscle spindles and Golgi tendon organs form a distributive impedance controller in the spinal cord that controls limb impedance and coordination during responses to external disturbances. These pathways include both monosynaptic and polysynaptic components. Autogenic, monosynaptic pathways serve to control the spring-like properties of muscles preserving the nonlinear relationship between stiffness and force. Intermuscular monosynaptic pathways compensate for inertial disparities between the inertial properties of limb segments and help to control inertial coupling between joints and axes of rotation. Reciprocal inhibition controls joint stiffness in conjunction with feedforward cocontraction commands. Excitatory force feedback becomes operational during locomotion and increases muscular stiffness to accommodate the higher inertial loads. Inhibitory force feedback is widely distributed among muscles. It is integrated with excitatory pathways from muscle spindles and Golgi tendon organs to determine limb stiffness and interjoint coordination during interactions with the environment. The intermuscular distribution of force feedback is variable and serves to modulate limb stiffness to meet the physical demands of different motor tasks. © 2024 American Physiological Society. Compr Physiol 14:5789-5838, 2024.

The proper development and function of the placenta are essential for the success of pregnancy and the well-being of both the fetus and the mother. Placental vascular function facilitates efficient fetal development during pregnancy by ensuring adequate gas exchange with low vascular resistance. This review focuses on how placental vascular function can be compromised in the pregnancy pathology preeclampsia, and conversely, how placental vascular dysfunction might contribute to this condition. While the maternal endothelium is widely recognized as a key focus in preeclampsia research, this review emphasizes the importance of understanding how this condition affects the development and function of the fetal placental vasculature. The placental vascular bed, consisting of microvasculature and macrovasculature, is discussed in detail, as well as structural and functional changes associated with preeclampsia. The complexity of placental vascular reactivity and function, its mediators, its impact on placental exchange and blood distribution, and how these factors are most affected in early-onset preeclampsia are further explored. These factors include foremost lipoproteins and their cargo, oxygen levels and oxidative stress, biomechanics, and shear stress. Challenges in studying placental pathophysiology are discussed, highlighting the necessity of innovative research methodologies, including ex vivo experiments, in vivo imaging tools, and computational modeling. Finally, an outlook on the potential of drug interventions targeting the placental endothelium to improve placental vascular function in preeclampsia is provided. Overall, this review highlights the need for further research and the development of models and tools to better understand and address the challenges posed by preeclampsia and its effects on placental vascular function to improve short- and long-term outcomes for the offspring of preeclamptic pregnancies. © 2024 American Physiological Society. Compr Physiol 14:5763-5787, 2024.

The rare disease Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in the genes encoding Cullin 3 (CUL3), Kelch-Like 3 (KLHL3), and two members of the With-No-Lysine [K] (WNK) kinase family, WNK1 and WNK4. In the kidney, these mutations ultimately cause hyperactivation of NCC along the renal distal convoluted tubule. Hypertension results from increased NaCl retention, and hyperkalemia by impaired K ⁺ secretion by downstream nephron segments. CUL3 and KLHL3 are now known to form a ubiquitin ligase complex that promotes proteasomal degradation of WNK kinases, which activate downstream kinases that phosphorylate and thus activate NCC. For CUL3, potent effects on the vasculature that contribute to the more severe hypertensive phenotype have also been identified. Here we outline the in vitro and in vivo studies that led to the discovery of the molecular pathways regulating NCC and vascular tone, and how FHHt-causing mutations disrupt these pathways. Potential mechanisms for variability in disease severity related to differential effects of each mutation on the kidney and vasculature are described, and other possible effects of the mutant proteins beyond the kidney and vasculature are explored. © 2024 American Physiological Society. Compr Physiol 14:5839-5874, 2024.

From the results of well-performed population health studies, we now have excellent data demonstrating that deficits in adult lung function may be present early in life, possibly as a result of developmental disorders, incurring a lifelong risk of obstructive airway diseases such as asthma and chronic obstructive pulmonary disease. Suboptimal fetal development results in intrauterine growth restriction and low birth weight at term (an outcome distinct from preterm complications), which are associated with subsequent obstructive disease. Numerous prenatal exposures and disorders compromise fetal development and these are summarized herein. Various physiological, structural, and mechanical abnormalities may result from prenatal disruption, including changes to airway smooth muscle structure-function, goblet cell biology, airway stiffness, geometry of the bronchial tree, lung parenchymal structure and mechanics, respiratory skeletal muscle contraction, and pulmonary inflammation. The literature therefore supports the need for early life intervention to prevent or correct growth defects, which may include simple nutritional or antioxidant therapy. © 2024 American Physiological Society. Compr Physiol 14:5729-5762, 2024.

For a long time, white adipocytes were thought to function as lipid storages due to the sizeable unilocular lipid droplet that occupies most of their space. However, recent discoveries have highlighted the critical role of white adipocytes in maintaining energy homeostasis and contributing to obesity and related metabolic diseases. These physiological and pathological functions depend heavily on the mitochondria that reside in white adipocytes. This article aims to provide an up-to-date overview of the recent research on the function and dysfunction of white adipocyte mitochondria. After briefly summarizing the fundamental aspects of mitochondrial biology, the article describes the protective role of functional mitochondria in white adipocyte and white adipose tissue health and various roles of dysfunctional mitochondria in unhealthy white adipocytes and obesity. Finally, the article emphasizes the importance of enhancing mitochondrial quantity and quality as a therapeutic avenue to correct mitochondrial dysfunction, promote white adipocyte browning, and ultimately improve obesity and its associated metabolic diseases. © 2024 American Physiological Society. Compr Physiol 14:5581-5640, 2024.

Preeclampsia, a pregnancy disorder characterized by de novo hypertension and maternal multisystem organ dysfunction, is the leading cause of maternal mortality worldwide and is associated with a fourfold greater risk of cardiovascular disease throughout the lifespan. Current understanding of the etiology of preeclampsia remains unclear, due in part to the varying phenotypical presentations of the disease, which has hindered the development of effective and mechanism-specific treatment or prevention strategies both during and after the affected pregnancy. These maternal sequelae of preeclampsia are symptoms of systemic vascular dysfunction in the maternal nonreproductive microvascular beds that drives the development and progression of adverse cardiovascular outcomes during preeclampsia. Despite normalization of vascular disturbances after delivery, subclinical dysfunction persists in the nonreproductive microvascular beds, contributing to an increased lifetime risk of cardiovascular and metabolic diseases and all-cause mortality. Given that women with a history of preeclampsia demonstrate vascular dysfunction despite an absence of traditional CVD risk factors, an understanding of the underlying mechanisms of microvascular dysfunction during and after preeclampsia is essential to identify potential therapeutic avenues to mitigate or reverse the development of overt disease. This article aims to provide a summary of the existing literature on the pathophysiology of maternal microvascular dysfunction during preeclampsia, the mechanisms underlying the residual dysfunction that remains after delivery, and current and potential treatments both during and after the affected pregnancy that may reduce microvascular dysfunction in these high-risk women. © 2024 American Physiological Society. Compr Physiol 14:5703-5727, 2024.

Neuromuscular transmission is the process by which motor neurons activate muscle contraction and thus plays an essential role in generating the purposeful body movements that aid survival. While many features of this process are common throughout the Animal Kingdom, such as the release of transmitter in multimolecular "quanta," and the response to it by opening ligand-gated postsynaptic ion channels, there is also much diversity between and within species. Much of this diversity is associated with specialization for either slow, sustained movements such as maintain posture or fast but brief movements used during escape or prey capture. In invertebrates, with hydrostatic and exoskeletons, most motor neurons evoke graded depolarizations of the muscle which cause graded muscle contractions. By contrast, vertebrate motor neurons trigger action potentials in the muscle fibers which give rise to all-or-none contractions. The properties of neuromuscular transmission, in particular the intensity and persistence of transmitter release, reflect these differences. Neuromuscular transmission varies both between and within individual animals, which often have distinct tonic and phasic subsystems. Adaptive plasticity of neuromuscular transmission, on a range of time scales, occurs in many species. This article describes the main steps in neuromuscular transmission and how they vary in a number of "model" species, including C. elegans , Drosophila , zebrafish, mice, and humans. © 2024 American Physiological Society. Compr Physiol 14:5641-5702, 2024.

Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic-rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521-5579, 2024.

The gut ecosystem, termed microbiota, is composed of bacteria, archaea, viruses, protozoa, and fungi and is estimated to outnumber human cells. Microbiota can affect the host by multiple mechanisms, including the synthesis of metabolites and toxins, modulating inflammation and interaction with other organisms. Advances in understanding commensal organisms' effect on human conditions have also elucidated the importance of this community for cardiovascular disease (CVD). This effect is driven by both direct CV effects and conditions known to increase CV risk, such as obesity, diabetes mellitus (DM), hypertension, and renal and liver diseases. Cardioactive metabolites, such as trimethylamine N -oxide (TMAO), short-chain fatty acids (SCFA), lipopolysaccharides, bile acids, and uremic toxins, can affect atherosclerosis, platelet activation, and inflammation, resulting in increased CV incidence. Interestingly, this interaction is bidirectional with microbiota affected by multiple host conditions including diet, bile acid secretion, and multiple diseases affecting the gut barrier. This interdependence makes manipulating microbiota an attractive option to reduce CV risk. Indeed, evolving data suggest that the benefits observed from low red meat and Mediterranean diet consumption can be explained, at least partially, by the changes that these diets may have on the gut microbiota. In this article, we depict the current epidemiological and mechanistic understanding of the role of microbiota and CVD. Finally, we discuss the potential therapeutic approaches aimed at manipulating gut microbiota to improve CV outcomes. © 2024 American Physiological Society. Compr Physiol 14:5449-5490, 2024.