Aging disrupts locus coeruleus-driven norepinephrine transmission in the prefrontal cortex: Implications for cognitive and motor decline.

The locus coeruleus (LC)-prefrontal cortex (PFC) circuitry is crucial for cognition, planning, posture and mobility. This study examines the role of norepinephrine (NE) in elucidating the neurobiological basis of age-related cognitive and motor declines. Aged mice exhibited reduced spatial learning, impaired memory, decreased physical endurance, and notable changes in locomotor behavior.

Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease.

Background: Alzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD.

Methods: We analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification.

Sex differences in single neuron function and proteomics profiles examined by patch-clamp and mass spectrometry in the locus coeruleus of the adult mouse.

Aims: This study aimed to characterize the properties of locus coeruleus (LC) noradrenergic neurons in male and female mice. We also sought to investigate sex-specific differences in membrane properties, action potential generation, and protein expression profiles to understand the mechanisms underlying neuronal excitability variations.

Methods: Utilizing a genetic mouse model by crossing Dbhcre knock-in mice with tdTomato Ai14 transgenic mice, LC neurons were identified using fluorescence microscopy.

Vitamin D Supplementation and Muscle Power, Strength and Physical Performance in Older Adults: A Randomized Controlled Trial.

Background: Low 25-hydroxyvitamin D (25[OH]D) concentrations (<30 ng/mL [<50 nmol/L]) have been associated with muscle weakness and impaired physical performance in observational studies. However, the effect of vitamin D supplementation on changes in muscle strength and physical performance in randomized controlled trials has been mixed.

Objectives: To determine the effect of daily vitamin D supplementation on leg power, strength, and physical performance in low-functioning older adults with 25(OH)D concentrations of 18 to <30 ng/mL.

Brainstem noradrenergic neurons: Identifying a hub at the intersection of cognition, motility, and skeletal muscle regulation.

Brainstem noradrenergic neuron clusters form a node integrating efferents projecting to distinct areas such as those regulating cognition and skeletal muscle structure and function, and receive dissimilar afferents through established circuits to coordinate organismal responses to internal and environmental challenges. Genetic lineage tracing shows the remarkable heterogeneity of brainstem noradrenergic neurons, which may explain their varied functions. They project to the locus coeruleus, the primary source of noradrenaline in the brain, which supports learning and cognition.

The association between aging-related monocyte transcriptional networks and comorbidity burden: the Multi-Ethnic Study of Atherosclerosis (MESA).

Translating our knowledge of the biological aging from animal models to humans may give rise to novel approaches of targeting multiple aging-related diseases simultaneously and increasing health span. Here, for the first time, we use transcriptomic signatures of monocytes to identify biological aging pathways underlying multiple aging-related diseases in humans. The ordinal logistic regression was used to cross-sectionally investigate transcriptomics of the comorbidity index in 1264 community-based Multi-Ethnic Study of Atherosclerosis (MESA) adults, 47% Caucasian, 32% Hispanic, 21% African American, and 51% female, aged 55-94 years.

Skeletal muscle sympathetic denervation disrupts the neuromuscular junction postterminal organization: A single-cell quantitative approach.

The sympathetic nervous system (SNS) regulates skeletal muscle motor innervation and stabilizes the NMJ in health, disease and aging. Previous studies using both chemical (6-hydroxydopamine, 6-OHDA) and microsurgically-induced sympathetic denervation examined the NMJ organization and transmission in the mouse; however, a detailed quantification of the postterminal on larger hindlimb muscles involved in gait mechanics and posture is lacking. The purpose of this study was to determine whether targets of the sympathetic neuron (SN) exhibiting different intrinsic composition such as the fast-twitch extensor digitorum longus (EDL) and the slow-twitch soleus muscles differ in their response to SN deprivation, and to develop a strategy to accurately quantify the impact of sympathectomy on the NMJ postterminal including those fibers located deeper in the muscle.

Long-term, induced expression of Hand2 in peripheral sympathetic neurons ameliorates sarcopenia in geriatric mice.

Background: The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle-wasting conditions such as sarcopenia, the age-dependent decline in muscle mass, force, and power. Devising interventions that can adjust neurotransmitter release to changing physiological demands will require understanding how the sympathetic nervous system affects muscle motor innervation and muscle mass, which will prevent sarcopenia-associated impaired mobility, falls, institutionalization, co-morbidity, and premature death.

Sarcopenia is associated with incident Alzheimer's dementia, mild cognitive impairment, and cognitive decline.

Objective: We examined whether sarcopenia is associated with the occurrence of late-life cognitive impairment.

Methods: Nondemented older adults (N = 1175) underwent annual testing with 17 cognitive tests summarized as a global cognitive score. A composite sarcopenia score was constructed based on muscle mass measured with bioelectrical impedance and muscle function based on grip strength.

The emerging role of the sympathetic nervous system in skeletal muscle motor innervation and sarcopenia.

Examining neural etiologic factors'role in the decline of neuromuscular function with aging is essential to our understanding of the mechanisms underlying sarcopenia, the age-dependent decline in muscle mass, force and power. Innervation of the skeletal muscle by both motor and sympathetic axons has been established, igniting interest in determining how the sympathetic nervous system (SNS) affect skeletal muscle composition and function throughout the lifetime. Selective expression of the heart and neural crest derivative 2 gene in peripheral SNs increases muscle mass and force regulating skeletal muscle sympathetic and motor innervation; improving acetylcholine receptor stability and NMJ transmission; preventing inflammation and myofibrillar protein degradation; increasing autophagy; and probably enhancing protein synthesis.

Motor function is the primary driver of the associations of sarcopenia and physical frailty with adverse health outcomes in community-dwelling older adults.

Background: This study tested the hypothesis that sarcopenia and its constituent components, reduced lean muscle mass and impaired motor function, are associated with reduced survival and increased risk of incident disabilities.

Methods: 1466 community-dwelling older adults underwent assessment of muscle mass with bioelectrical impedance analysis (BIA), grip strength, gait speed and other components of physical frailty and annual self-report assessments of disability. We used Cox proportional hazards models that controlled for age, sex, race, education and height to examine the associations of a continuous sarcopenia metric with the hazard of death and incident disabilities.

Heart and neural crest derivative 2-induced preservation of sympathetic neurons attenuates sarcopenia with aging.

Background: Sarcopenia, or age-dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, co-morbidity, and premature death. The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system (SNS) neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle-wasting conditions.

Postganglionic sympathetic neurons, but not locus coeruleus optostimulation, activates neuromuscular transmission in the adult mouse in vivo.

Recent work demonstrated that sympathetic neurons innervate the skeletal muscle near the neuromuscular junction (NMJ), and muscle sympathectomy and sympathomimetic agents strongly influence motoneuron synaptic vesicle release ex vivo. Moreover, reports attest that the pontine nucleus locus coeruleus (LC) projects to preganglionic sympathetic neurons and regulates human mobility and skeletal muscle physiology. Thus, we hypothesized that peripheral and central sympathetic neurons projecting directly or indirectly to the skeletal muscle regulate NMJ transmission.

Semiautomatic morphometric analysis of skeletal muscle obtained by needle biopsy in older adults.

Analysis of skeletal muscle mass and composition is essential for studying the biology of age-related sarcopenia, loss of muscle mass, and function. Muscle immunohistochemistry (IHC) allows for simultaneous visualization of morphological characteristics and determination of fiber type composition. The information gleaned from myosin heavy chain (MHC) isoform, and morphological measurements offer a more complete assessment of muscle health and properties than classical techniques such as SDS-PAGE and ATPase immunostaining; however, IHC quantification is a time-consuming and tedious method.

Bidirectional Control of Alcohol-drinking Behaviors Through Locus Coeruleus Optoactivation.

The relationship between stress and alcohol-drinking behaviors has been intensively explored; however, neuronal substrates and neurotransmitter dynamics responsible for a causal link between these conditions are still unclear. Here, we optogenetically manipulated locus coeruleus (LC) norepinephrine (NE) activity by applying distinct stimulation protocols in order to explore how phasic and tonic NE release dynamics control alcohol-drinking behaviors. Our results clearly demonstrate contrasting behavioral consequences of LC-NE circuitry activation during low and high frequency stimulation.

Aging Blunts Sympathetic Neuron Regulation of Motoneurons Synaptic Vesicle Release Mediated by β1- and α2B-Adrenergic Receptors in Geriatric Mice.

This study was designed to determine whether and how the sympathetic nervous system (SNS) regulates motoneuron axon function and neuromuscular transmission in young (3-4-month) and geriatric (31-month) mice. Our approach included sciatic-peroneal nerve immunolabeling coregistration, and electrophysiological recordings in a novel mouse ex-vivo preparation, the sympathetic-peroneal nerve-lumbricalis muscle (SPNL). Here, the interaction between the motoneuron and SNS at the neuromuscular junction (NMJ) and muscle innervation reflect the complexity of the living mouse.

Sympathomimetics regulate neuromuscular junction transmission through TRPV1, P/Q- and N-type Ca channels.

Increasing evidence indicates that, first, the sympathetic nervous system interacts extensively with both vasculature and skeletal muscle fibers near neuromuscular junctions (NMJs) and, second, its neurotransmitter, noradrenaline, influences myofiber molecular composition and function and motor innervation. Since sympathomimetic agents have been reported to improve NMJ transmission, we examined whether two in clinical use, salbutamol and clenbuterol, affect the motor axon terminal via extracellular Ca and molecular targets, such as TRPV1 and P/Q- and N-type voltage-activated Ca channels. Electrophysiological recordings in ex-vivo preparations of peroneal nerves and lumbricalis muscles from young adult mice focused on spontaneous miniature end-plate potentials and singly and repetitively evoked end-plate potentials.

The sympathetic nervous system regulates skeletal muscle motor innervation and acetylcholine receptor stability.

Aim: Symptoms of autonomic failure are frequently the presentation of advanced age and neurodegenerative diseases that impair adaptation to common physiologic stressors. The aim of this work was to examine the interaction between the sympathetic and motor nervous system, the involvement of the sympathetic nervous system (SNS) in neuromuscular junction (NMJ) presynaptic motor function, the stability of postsynaptic molecular organization, and the skeletal muscle composition and function.

Methods: Since muscle weakness is a symptom of diseases characterized by autonomic dysfunction, we studied the impact of regional sympathetic ablation on muscle motor innervation by using transcriptome analysis, retrograde tracing of the sympathetic outflow to the skeletal muscle, confocal and electron microscopy, NMJ transmission by electrophysiological methods, protein analysis, and state of the art microsurgical techniques, in C57BL6, MuRF1KO and Thy-1 mice.

Perivascular cell αv integrins as a target to treat skeletal muscle fibrosis.

Fibrosis following injury leads to aberrant regeneration and incomplete functional recovery of skeletal muscle, but the lack of detailed knowledge about the cellular and molecular mechanisms involved hampers the design of effective treatments. Using state-of-the-art technologies, Murray et al. (2017) found that perivascular PDGFRβ-expressing cells generate fibrotic cells in the skeletal muscle.

Troponin T3 associates with DNA consensus sequence that overlaps with p53 binding motifs.

We recently reported that in addition to its classical cytoplasmic location, the fast skeletal muscle Troponin T3 (TnT3) shuttles to the nucleus, where it appears to perform nonclassical transcription regulatory functions. Importantly, changes in the composition of the nucleus-localized pool of TnT3 and its fragments contribute to age-dependent muscle damage and wasting. Here, using ChIP-Seq, we demonstrate that TnT3 associates with DNA consensus sequences including the TGCCT motif, which is required for p53 binding to the promoter area of p53-related genes.

Relationship of Physical Function to Single Muscle Fiber Contractility in Older Adults: Effects of Resistance Training With and Without Caloric Restriction.

Background: Previous studies support beneficial effects of both resistance exercise training (RT) and caloric restriction (CR) on skeletal muscle strength and physical performance. The goal of this study was to determine the effects of adding CR to RT on single-muscle fiber contractility responses to RT in older overweight and obese adults.

Methods: We analyzed contractile properties in 1,253 single myofiber from muscle biopsies of the vastus lateralis, as well as physical performance and thigh muscle volume, in 31 older (65-80 years), overweight or obese (body mass index = 27-35 kg/m2) men (n = 19) and women (n = 12) who were randomly assigned to a standardized, progressive RT intervention with CR (RT+CR; n = 15) or without CR (RT; n = 16) for 5 months.

How Plastic Are Pericytes?

Pericytes are defined by both their anatomical location and molecular markers. Numerous publications have reported their role as stem cells, contributing to the formation of tissues other than blood vessels. However, using cell-lineage tracing in a new transgenic mouse model, a recent study shows that in the context of aging and some pathologies, Tbx18+ pericytes do not function as stem cells in vivo.

Pericytes are heterogeneous in their origin within the same tissue.

Pericytes heterogeneity is based on their morphology, distribution, and markers. It is well known that pericytes from different organs may have distinct embryonic sources. Yamazaki et al.

Cardiac troponin T and fast skeletal muscle denervation in ageing.

Background: Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown.