Chronic aryl hydrocarbon receptor activity impairs muscle mitochondrial function with tobacco smoking.

Background: Accumulating evidence has demonstrated that chronic tobacco smoking directly contributes to skeletal muscle dysfunction independent of its pathological impact to the cardiorespiratory systems. The mechanisms underlying tobacco smoke toxicity in skeletal muscle are not fully resolved. In this study, the role of the aryl hydrocarbon receptor (AHR), a transcription factor known to be activated with tobacco smoke, was investigated.

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.

Background: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle.

Methods: We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls.

Temporal serum metabolomic and lipidomic analyses distinguish patients with access-related hand disability following arteriovenous fistula creation.

For end-stage kidney disease (ESKD) patients, hemodialysis requires durable vascular access which is often surgically created using an arteriovenous fistula (AVF). However, some ESKD patients that undergo AVF placement develop access-related hand dysfunction (ARHD) through unknown mechanisms. In this study, we sought to determine if changes in the serum metabolome could distinguish ESKD patients that develop ARHD from those that have normal hand function following AVF creation.

-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.

The objective of the present study was to determine if treatment with -acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment.

IGF-1 Therapy Improves Muscle Size and Function in Experimental Peripheral Arterial Disease.

Lower-extremity peripheral arterial disease (PAD) has increased in prevalence, yet therapeutic development has remained stagnant. Skeletal muscle health and function has been strongly linked to quality of life and medical outcomes in patients with PAD. Using a rodent model of PAD, this study demonstrates that treatment of the ischemic limb with insulin-like growth factor (IGF)-1 significantly increases muscle size and strength without improving limb hemodynamics.

Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease.

Background: Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD.

Chronic activation of the aryl hydrocarbon receptor in muscle exacerbates ischemic pathology in chronic kidney disease.

Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the cellular and physiological mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic toxins, many of which are ligands for the aryl hydrocarbon receptor (AHR), are associated with adverse limb outcomes in PAD.

Influences of renal insufficiency and ischemia on mitochondrial bioenergetics and limb dysfunction in a novel murine iliac arteriovenous fistula model.

Objective: Hand disability after hemodialysis access surgery has been common yet has remained poorly understood. Arteriovenous fistula (AVF) hemodynamic perturbations have not reliably correlated with the observed measures of hand function. Chronic kidney disease (CKD) is known to precipitate myopathy; however, the interactive influences of renal insufficiency and ischemia on limb outcomes have remained unknown.

The Role of Mitochondrial and Redox Alterations in the Skeletal Myopathy Associated with Chronic Kidney Disease.

An estimated 700 million people globally suffer from chronic kidney disease (CKD). In addition to increasing cardiovascular disease risk, CKD is a catabolic disease that results in a loss of muscle mass and function, which are strongly associated with mortality and a reduced quality of life. Despite the importance of muscle health and function, there are no treatments available to prevent or attenuate the myopathy associated with CKD.

Metabolomic profiling reveals muscle metabolic changes following iliac arteriovenous fistula creation in mice.

End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood.

A Murine Model of Hemodialysis Access-related Hand Dysfunction.

Chronic kidney disease is a major public health problem, and the prevalence of end-stage renal disease (ESRD) requiring chronic renal replacement therapies such as hemodialysis continues to increase. Autogenous arteriovenous fistula (AVF) placement remains a primary vascular access option for ESRD patients. Unfortunately, approximately half of the hemodialysis patients experience dialysis access-related hand dysfunction (ARHD), ranging from subtle paresthesia to digital gangrene.

Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb.

Background: Despite improved surgical approaches for chronic limb-threatening ischemia (CLTI), amputation rates remain high and contributing tissue-level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation.

Methods And Results: Gastrocnemius muscle was collected from non-ischemic controls (n = 19) and either pre-interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients.

Development of a murine iliac arteriovenous fistula model for examination of hemodialysis access-related limb pathophysiology.

Objective: Hemodialysis access-related hand dysfunction is a common clinical feature of patients with chronic kidney disease (CKD) after arteriovenous fistula (AVF) placement. The heterogeneity in symptoms and the lack of a predictive association with changes in hemodynamic alterations precipitated by the AVF suggest that other factors are involved in the mechanisms responsible for causing hand and limb dysfunction postoperatively. To the best of our knowledge, no suitable animal models have provided a platform for performing preclinical experiments designed to elucidate the biologic drivers of access-related hand dysfunction.

Skeletal myopathy in CKD: a comparison of adenine-induced nephropathy and 5/6 nephrectomy models in mice.

Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice ( = 5-9 mice/sex/group) were randomly allocated to CKD groups (0.

Neither Peristaltic Pulse Dynamic Compressions nor Heat Therapy Accelerate Glycogen Resynthesis after Intermittent Running.

Purpose: To investigate the effects of a single session of either peristaltic pulse dynamic leg compressions (PPDC) or local heat therapy (HT) after prolonged intermittent shuttle running on skeletal muscle glycogen content, muscle function, and the expression of factors involved in skeletal muscle remodeling.

Methods: Twenty-six trained individuals were randomly allocated to either a PPDC (n = 13) or a HT (n = 13) group. After completing a 90-min session of intermittent shuttle running, participants consumed 0.

Unique Metabolomic Profile of Skeletal Muscle in Chronic Limb Threatening Ischemia.

Chronic limb threatening ischemia (CLTI) is the most severe manifestation of peripheral atherosclerosis. Patients with CLTI have poor muscle quality and function and are at high risk for limb amputation and death. The objective of this study was to interrogate the metabolome of limb muscle from CLTI patients.

Skeletal Muscle Mitochondrial Dysfunction and Oxidative Stress in Peripheral Arterial Disease: A Unifying Mechanism and Therapeutic Target.

Peripheral artery disease (PAD) is caused by atherosclerosis in the lower extremities, which leads to a spectrum of life-altering symptomatology, including claudication, ischemic rest pain, and gangrene requiring limb amputation. Current treatments for PAD are focused primarily on re-establishing blood flow to the ischemic tissue, implying that blood flow is the decisive factor that determines whether or not the tissue survives. Unfortunately, failure rates of endovascular and revascularization procedures remain unacceptably high and numerous cell- and gene-based vascular therapies have failed to demonstrate efficacy in clinical trials.

Heat therapy improves body composition and muscle function but does not affect capillary or collateral growth in a model of obesity and hindlimb ischemia.

Heat therapy (HT) has emerged as a potential adjunctive therapy to alleviate the symptoms of peripheral artery disease (PAD), but the mechanisms underlying the positive effects of this treatment modality remain undefined. Using a model of diet-induced obesity (DIO) and ischemia-induced muscle damage, we tested the hypothesis that HT would alter body composition, promote vascular growth and mitochondrial biogenesis, and improve skeletal muscle function. Male DIO C57Bl/6J mice underwent bilateral ligation of the femoral artery and were randomly allocated to receive HT or a control intervention for 30 min daily over 3 wk.

Local Heat Therapy to Accelerate Recovery After Exercise-Induced Muscle Damage.

The prolonged impairment in muscle strength, power, and fatigue resistance after eccentric exercise has been ascribed to a plethora of mechanisms, including delayed muscle refueling and microvascular and mitochondrial dysfunction. This review explores the hypothesis that local heat therapy hastens functional recovery after strenuous eccentric exercise by facilitating glycogen resynthesis, reversing vascular derangements, augmenting mitochondrial function, and stimulating muscle protein synthesis.

Skeletal muscle adaptations to heat therapy.

The therapeutic effects of heat have been harnessed for centuries to treat skeletal muscle disorders and other pathologies. However, the fundamental mechanisms underlying the well-documented clinical benefits associated with heat therapy (HT) remain poorly defined. Foundational studies in cultured skeletal muscle and endothelial cells, as well as in rodents, revealed that episodic exposure to heat stress activates a number of intracellular signaling networks and promotes skeletal muscle remodeling.

Effects of repeated local heat therapy on skeletal muscle structure and function in humans.

The purpose of the present study was to examine the effects of repeated exposure to local heat therapy (HT) on skeletal muscle function, myofiber morphology, capillarization, and mitochondrial content in humans. Twelve young adults (23.6 ± 4.

Heat therapy improves soleus muscle force in a model of ischemia-induced muscle damage.

Leg muscle ischemia in patients with peripheral artery disease (PAD) leads to alterations in skeletal muscle morphology and reduced leg strength. We tested the hypothesis that exposure to heat therapy (HT) would improve skeletal muscle function in a mouse model of ischemia-induced muscle damage. Male 42-wk-old C57Bl/6 mice underwent ligation of the femoral artery and were randomly assigned to receive HT (immersion in a water bath at 37°C, 39°C, or 41°C for 30 min) or a control intervention for 3 wk.

Impact of heat therapy on recovery after eccentric exercise in humans.

The purpose of this study was to investigate the effects of heat therapy (HT) on functional recovery, the skeletal muscle expression of angiogenic factors, macrophage content, and capillarization after eccentric exercise in humans. Eleven untrained individuals (23.8 ± 0.

Heat therapy promotes the expression of angiogenic regulators in human skeletal muscle.

Heat therapy has been shown to promote capillary growth in skeletal muscle and in the heart in several animal models, but the effects of this therapy on angiogenic signaling in humans are unknown. We evaluated the acute effect of lower body heating (LBH) and unilateral thigh heating (TH) on the expression of angiogenic regulators and heat shock proteins (HSPs) in healthy young individuals. Exposure to LBH (n = 18) increased core temperature (Tc) from 36.