Comprehensive Physiology最新文献

Electrical mechanosensing is a process mediated by specialized ion channels, gated directly or indirectly by mechanical forces, which allows cells to detect and subsequently respond to mechanical stimuli. The activation of mechanosensitive (MS) ion channels, intrinsically gated by mechanical forces, or mechanoresponsive (MR) ion channels, indirectly gated by mechanical forces, results in electrical signaling across lipid bilayers, such as the plasma membrane. While the functions of mechanically gated channels within a sensory context (e.g., proprioception and touch) are well described, there is emerging data demonstrating functions beyond touch and proprioception, including mechanoregulation of intracellular signaling and cellular/systemic metabolism. Both MR and MS ion channel signaling have been shown to contribute to the regulation of metabolic dysfunction, including obesity, insulin resistance, impaired insulin secretion, and inflammation. This review summarizes our current understanding of the contributions of several MS/MR ion channels in cell types implicated in metabolic dysfunction, namely, adipocytes, pancreatic β-cells, hepatocytes, and skeletal muscle cells, and discusses MS/MR ion channels as possible therapeutic targets. © 2024 American Physiological Society. Compr Physiol 14:5269-5290, 2024.

The human sensorimotor control system has exceptional abilities to perform skillful actions. We easily switch between strenuous tasks that involve brute force, such as lifting a heavy sewing machine, and delicate movements such as threading a needle in the same machine. Using a structure with different control architectures, the motor system is capable of updating its ability to perform through our daily interaction with the fluctuating environment. However, there are issues that make this a difficult computational problem for the brain to solve. The brain needs to control a nonlinear, nonstationary neuromuscular system, with redundant and occasionally undesired degrees of freedom, in an uncertain environment using a body in which information transmission is subject to delays and noise. To gain insight into the mechanisms of motor control, here we survey movement laws and invariances that shape our everyday motion. We then examine the major solutions to each of these problems in the three parts of the sensorimotor control system, sensing, planning, and acting. We focus on how the sensory system, the control architectures, and the structure and operation of the muscles serve as complementary mechanisms to overcome deviations and disturbances to motor behavior and give rise to skillful motor performance. We conclude with possible future research directions based on suggested links between the operation of the sensorimotor system across the movement stages. © 2024 American Physiological Society. Compr Physiol 14:5179-5224, 2024.

Red blood cell (RBC) trapping describes the accumulation of RBCs in the microvasculature of the kidney outer medulla that occurs following ischemic acute kidney injury (AKI). Despite its prominence in human kidneys following AKI, as well as evidence from experimental models demonstrating that the severity of RBC trapping is directly correlated with renal recovery, to date, RBC trapping has not been a primary focus in understanding the pathogenesis of ischemic kidney injury. New evidence from rodent models suggests that RBC trapping is responsible for much of the tubular injury occurring in the initial hours after kidney reperfusion from ischemia. This early injury appears to result from RBC cytotoxicity and closely reflects the injury profile observed in human kidneys, including sloughing of the medullary tubules and the formation of heme casts in the distal tubules. In this review, we discuss what is currently known about RBC trapping. We conclude that RBC trapping is likely avoidable. The primary causes of RBC trapping are thought to include rheologic alterations, blood coagulation, tubular cell swelling, and increased vascular permeability; however, new data indicate that a mismatch in blood flow between the cortex and medulla where medullary perfusion is maintained during cortical ischemia is also likely critical. The mechanism(s) by which RBC trapping contributes to renal functional decline require more investigation. We propose a renewed focus on the mechanisms mediating RBC trapping, and RBC trapping-associated injury is likely to provide important knowledge for improving AKI outcomes. © 2024 American Physiological Society. Compr Physiol 14:5325-5343, 2024.

Acquired brain injuries, such as ischemic stroke, intracerebral hemorrhage (ICH), and traumatic brain injury (TBI), can cause severe neurologic damage and even death. Unfortunately, currently, there are no effective and safe treatments to reduce the high disability and mortality rates associated with these brain injuries. However, environmental enrichment (EE) is an emerging approach to treating and rehabilitating acquired brain injuries by promoting motor, sensory, and social stimulation. Multiple preclinical studies have shown that EE benefits functional recovery, including improved motor and cognitive function and psychological benefits mediated by complex protective signaling pathways. This article provides an overview of the enriched environment protocols used in animal models of ischemic stroke, ICH, and TBI, as well as relevant clinical studies, with a particular focus on ischemic stroke. Additionally, we explored studies of animals with stroke and TBI exposed to EE alone or in combination with multiple drugs and other rehabilitation modalities. Finally, we discuss the potential clinical applications of EE in future brain rehabilitation therapy and the molecular and cellular changes caused by EE in rodents with stroke or TBI. This article aims to advance preclinical and clinical research on EE rehabilitation therapy for acquired brain injury. © 2024 American Physiological Society. Compr Physiol 14:5291-5323, 2024.

Purine nucleotides play central roles in energy metabolism in the heart. Most fundamentally, the free energy of hydrolysis of the adenine nucleotide adenosine triphosphate (ATP) provides the thermodynamic driving force for numerous cellular processes including the actin-myosin crossbridge cycle. Perturbations to ATP supply and/or demand in the myocardium lead to changes in the homeostatic balance between purine nucleotide synthesis, degradation, and salvage, potentially affecting myocardial energetics and, consequently, myocardial mechanics. Indeed, both acute myocardial ischemia and decompensatory remodeling of the myocardium in heart failure are associated with depletion of myocardial adenine nucleotides and with impaired myocardial mechanical function. Yet there remain gaps in the understanding of mechanistic links between adenine nucleotide degradation and contractile dysfunction in heart disease. The scope of this article is to: (i) review current knowledge of the pathways of purine nucleotide depletion and salvage in acute ischemia and in chronic heart disease; (ii) review hypothesized mechanisms linking myocardial mechanics and energetics with myocardial adenine nucleotide regulation; and (iii) highlight potential targets for treating myocardial metabolic and mechanical dysfunction associated with these pathways. It is hypothesized that an imbalance in the degradation, salvage, and synthesis of adenine nucleotides leads to a net loss of adenine nucleotides in both acute ischemia and under chronic high-demand conditions associated with the development of heart failure. This reduction in adenine nucleotide levels results in reduced myocardial ATP and increased myocardial inorganic phosphate. Both of these changes have the potential to directly impact tension development and mechanical work at the cellular level. © 2024 American Physiological Society. Compr Physiol 14:5345-5369, 2024.

According to the Centers for Disease Control and Prevention, 1 in 2 U.S. adults have hypertension, and more than 1 in 7 chronic kidney disease. In fact, hypertension is the second leading cause of kidney failure in the United States; it is a complex disease characterized by, leading to, and caused by renal dysfunction. It is well-established that hypertensive renal damage is accompanied by mitochondrial damage and oxidative stress, which are differentially regulated and manifested along the nephron due to the diverse structure and functions of renal cells. This article provides a summary of the relevant knowledge of mitochondrial bioenergetics and metabolism, focuses on renal mitochondrial function, and discusses the evidence that has been accumulated regarding the role of epithelial mitochondrial bioenergetics in the development of renal tissue dysfunction in hypertension. © 2024 American Physiological Society. Compr Physiol 14:5225-5242, 2024.

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of IR in patients with CKD, and recent type 2 diabetic trials with implications for improved cardiovascular outcomes in CKD. © 2023 American Physiological Society. Compr Physiol 13:5069-5076, 2023.

The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive disorder of pregnancy, has been associated with an increased risk of future disease, including cardiovascular and kidney diseases. Cellular senescence, the process of cell cycle arrest in response to many physiologic and maladaptive stimuli, may play an important role in the pathogenesis of preeclampsia and provide a mechanistic link to future disease. In this article, we will discuss the pathophysiology of preeclampsia, the many mechanisms of cellular senescence, evidence for the involvement of senescence in the development of preeclampsia, as well as evidence that cellular senescence may link preeclampsia to the risk of future disease. Lastly, we will explore how a better understanding of the role of cellular senescence in preeclampsia may lead to therapeutic trials. © 2023 American Physiological Society. Compr Physiol 13:5077-5114, 2023.

Exercise capacity of an individual describes the ability to perform physical activity. This exercise capacity is influenced by intrinsic factors such as genetic constitution and extrinsic factors such as exercise training. On the metabolic level exercise and metabolism are linked. As an important site of metabolism and the main source for ATP needed for muscle contraction, mitochondrial function can determine exercise capacity, and exercise inversely influences mitochondrial function. It has been suggested that exercise mediates many of its effects due to such metabolic changes. Although extrinsic factors affect exercise capacity, a major part of an individual's exercise capacity is genetically determined, and extrinsic factors can only improve on this baseline. Looking at the effect of exercise capacity on and with disease, the two go hand in hand. On one hand, disease is negatively affecting an individual's exercise capacity; on the other hand, exercise offers an effective treatment option. Combining these factors, exercise capacity is an often-ignored prognostic variable for life expectancy as well as morbidity and mortality. In this review, we aim to provide the current knowledge on the links between inherited and acquired exercise capacity, as well as the mechanisms in which metabolism interacts with exercise capacity. © 2023 American Physiological Society. Compr Physiol 13:5115-5155, 2023.

The lung is an inherently mechanosensitive organ, where cells of the airway and parenchyma experience a range of mechanical forces throughout life including shear, stretch, and compression, in both health and disease. In this regard, pediatric and adult lung diseases such as wheezing and asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) all involve macroscopic and cellular changes to the mechanical properties of the bronchial airways and/or parenchyma to varying extents. Accordingly, understanding how mechanical forces are sensed in the lung, and the responses of cells and tissues in the context of normal development and health versus disease conditions becomes highly relevant. There is increasing recognition that transduction of mechanical forces into cellular responses involves a number of channels, some of which are inherently mechanosensitive. Such channels trigger mechanotransduction pathways that may further mediate cellular remodeling, inflammation, and other pathophysiologic mechanisms in response to stretch, stiffness, and inflammatory cascades. Two particularly important channel families have emerged in pulmonary pathophysiology: the transient receptor potential vanilloid family with focus on member TRPV4 and the recently identified Piezo (PZ) channels. Here, we explore current understanding of the contributions of TRPV4 and PZ channels in lung health and disease states, focusing on the interactions between these mechanosensitive channels and their local environment including immune cells, the extracellular matrix, and cellular cytoskeletal elements. We further discuss potential areas for future research to better understand the impact of mechanical channels on pulmonary health and disease. © 2023 American Physiological Society. Compr Physiol 13:5157-5178, 2023.