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The architecture of a neuromuscular junction (NMJ). (A, B) The NMJ is composed of three elements: pre-synaptic (motor nerve terminal), intrasynaptic (synaptic basal lamina), and post-synaptic component (muscle fiber and muscle membrane) (Punga and Ruegg, 2012). When the action potential reaches the motor nerve terminal the calcium channels open and the calcium enters in the neuron and delivers ACh in the synaptic cleft. (C) AChR activates the DHPRs located in the sarcolemma and by induction the RyRs. Calcium released from the sarcoplasmic reticulum through the RyRs binds to troponin C and allows cross-bridge cycling and force production.
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Aging is associated with a progressive loss of muscle mass and strength and a decline in neurophysiological functions. Age-related neuromuscular junction (NMJ) plays a key role in musculoskeletal impairment that occurs with aging. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. Many...
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... The neuromuscular system is composed of individual motor units, each consisting of a single motor neuron, a neuromuscular junction (NMJ), and muscle fibres innervated by the motor neuron. Diminished motor unit function and decreased muscle volume are hallmarks of several neuromuscular disorders [1] and of sarcopenia, the age-associated loss of skeletal muscle mass and function [2]. Gradual loss of skeletal muscle capacity has been reported in invertebrates, rodents and humans [3][4][5], with intrinsic mechanisms regulating age-related muscle dysfunction largely conserved across species [6]. ...
... Gradual loss of skeletal muscle capacity has been reported in invertebrates, rodents and humans [3][4][5], with intrinsic mechanisms regulating age-related muscle dysfunction largely conserved across species [6]. Age-related muscle loss is accompanied by progressive modifications in the structure and function of the NMJ, the specialized synapse at the interface between the nervous and muscular system [1], with the resulting uncoupling of the excitation-contraction machinery [7,8]. In mammals, including humans, these modifications include changes in the branching pattern of the motor nerve terminal that contacts the myofibre, fragmented NMJ architecture, impaired synaptic neurotransmitter distribution, and decreased density of presynaptic active zone markers [9][10][11][12][13]. Functionally, aged mammalian NMJs exhibit increased failures in evoked release [14], changes in quantal release [15] and a slowing-down of axoplasmic transport of proteins [16]. ...
Alterations in the neuromuscular system underlie several neuromuscular diseases and play critical roles in the development of sarcopenia, the age-related loss of muscle mass and function. Mammalian Myostatin (MST) and GDF11, members of the TGF-β superfamily of growth factors, are powerful regulators of muscle size in both model organisms and humans. Myoglianin (MYO), the Drosophila homologue of MST and GDF11, is a strong inhibitor of synaptic function and structure at the neuromuscular junction in flies. Here, we identified Plum, a transmembrane cell surface protein, as a modulator of MYO function in the larval neuromuscular system. Reduction of Plum in the larval body-wall muscles abolishes the previously demonstrated positive effect of attenuated MYO signalling on both muscle size and neuromuscular junction structure and function. In addition, downregulation of Plum on its own results in decreased synaptic strength and body weight, classifying Plum as a (novel) regulator of neuromuscular function and body (muscle) size. These findings offer new insights into possible regulatory mechanisms behind ageing-and disease-related neuromuscular dysfunctions in humans and identify potential targets for therapeutic interventions.
... During aging, NMJs undergo dramatic morphological, functional, and molecular changes in both pre-synaptic and post-synaptic regions that lead them to ultimately degenerate [144][145][146]. ...
... However, this effect is not accompanied by increased ACh stores, since it has been demonstrated that as presynaptic branching increases with age, the quantity of available ACh declines [149,150]. At the post-synaptic level, the endplates decrease in size and are fragmented with a gradual decrease in the number of AChRs per junction, and the number and length of postsynaptic folds are reduced, leading to a functional impairment of NMJ response [132,[144][145][146][147][149][150][151][152]. Additionally, tSCs relocate from the motor nerve terminal and protrude branches toward the synaptic cleft, which leads to the neuromuscular system functional drop by aging [153,154]. ...
Skeletal muscle is characterized by a remarkable capacity to rearrange after physiological changes and efficiently regenerate. However, during aging, extensive injury, or pathological conditions, the complete regenerative program is severely affected, with a progressive loss of muscle mass and function, a condition known as sarcopenia. The compromised tissue repair program is attributable to the gradual depletion of stem cells and to altered regulatory signals. Defective muscle regeneration can severely affect re-innervation by motor axons, and neuromuscular junctions (NMJs) development, ultimately leading to skeletal muscle atrophy. Defects in NMJ formation and maintenance occur physiologically during aging and are responsible for the pathogenesis of several neuromuscular disorders. However, it is still largely unknown how neuromuscular connections are restored on regenerating fibers. It has been suggested that attractive and repelling signals used for axon guidance could be implicated in this process; in particular, guidance molecules called semaphorins play a key role. Semaphorins are a wide family of extracellular regulatory signals with a multifaceted role in cell-cell communication. Originally discovered as axon guidance factors, they have been implicated in cancer progression, embryonal organogenesis, skeletal muscle innervation, and other physiological and developmental functions in different tissues. In particular, in skeletal muscle, specific semaphorin molecules are involved in the restoration and remodeling of the nerve-muscle connections, thus emphasizing their plausible role to ensure the success of muscle regeneration. This review article aims to discuss the impact of aging on skeletal muscle regeneration and NMJs remodeling and will highlight the most recent insights about the role of semaphorins in this context.
... Physiological aging causes a decline of motor function due to losses of muscle mass and strength, denervation of neuromuscular junctions (NMJs), a loss of motor neurons in the spinal cord, and impairment of motor cortex function. Losses of muscle mass and strength (sarcopenia) are more pronounced in the elderly [3][4][5][6][7]. Meanwhile, a decline in motor function has been reported in studies of middle-aged humans and rodents. ...
Physiological aging causes a decline of motor function due to impairment of motor cortex function, losses of motor neurons and neuromuscular junctions, sarcopenia, and frailty. There is increasing evidence suggesting that the changes in motor function start earlier in the middle-aged stage. The mechanism underlining the middle-aged decline in motor function seems to relate to the central nervous system rather than the peripheral neuromuscular system. The motor cortex is one of the responsible central nervous systems for coordinating and learning motor functions. The neuronal circuits in the motor cortex show plasticity in response to motor learning, including LTP. This motor cortex plasticity seems important for the intervention method mechanisms that revert the age-related decline of motor function. This review will focus on recent findings on the role of plasticity in the motor cortex for motor function and age-related changes. The review will also introduce our recent identification of an age-related decline of neuronal activity in the primary motor cortex of middle-aged mice using electrophysiological recordings of brain slices.
... We evaluated NMJ innervation by looking at the NF fibers contacting the endplate (Fig. 5A). With aging NMJs are subjected to remodelling, showing a reduction in postsynaptic folds and nerve terminal area [30], together with fragmented AChRs and varicose nerve terminals [31] and denervation [32]. We discriminated among NMJs that appeared innervated, denervated or fragmented (see Fig. 5A and 5B for examples). ...
... Many pathways are involved in NMJ dysfunction processes, and in particular Agrin-MuSK signaling pathway has been investigated for its role in aging-related processes affecting NMJs [30]. Thus, we analysed the percentage of p-MuSK signal (volume) within the endplate (NMJ volume) (Fig. 7A, 7B) and we observed a significant increase (p<0.01) of p-MuSK signal in ActR-Fc-nLG3 compared to the other groups (Fig. 7B). ...
... Based on the encouraging results we obtained on young mice [23], we investigated the effects of chronic (5 week) administration of ActR-Fc-nLG3 to aged mice, focusing on muscle mass, endurance and strength. Aging in mice reduces motor performance mimicking the loss of muscle strength and function that occurs in aged humans [30]. Moreover, the reduced capability of the NMJ to respond to training-induced remodelling and the age-related reduced motility have been suggested as two of the many pathogenic bases of sarcopenia [20,36,37]. ...
Sarcopenia is the primary cause of impaired motor performance in the elderly. The current prevailing approach to counteract such condition is increasing the muscle mass through inhibition of the myostatin system: however, this strategy only moderately improves muscular strength, not being able to sustain the innervation of the hypertrophic muscle per se, leading to a progressive worsening of motor performances. Thus, we proposed the administration of ActR-Fc-nLG3, a protein that combines the soluble activin receptor, a strong myostatin inhibitor, with the C-terminal agrin nLG3 domain. This compound has the potential of reinforcing neuro-muscular stability to the hypertrophic muscle. We previously demonstrated an enhancement of motor endurance and ACh receptor aggregation in young mice after ActR-Fc-nLG3 administration. Now we extended these observations by demonstrating that also in aged (2 years-old) mice, long-term administration of ActR-Fc-nLG3 increases in a sustained way both motor endurance and muscle strength, compared with ActR-Fc, a myostatin inhibitor, alone. Histological data demonstrate that the administration of this biological improves neuromuscular stability and fiber innervation maintenance, preventing muscle fiber atrophy and inducing only moderate hypertrophy. Moreover, at the postsynaptic site we observe an increased folding in the soleplate, a likely anatomical substrate for improved neurotransmission efficiency in the NMJ, that may lead to enhanced motor endurance. We suggest that ActR-Fc-nLG3 may become a valid option for treating sarcopenia and possibly other disorders of striatal muscles.
... The NMJ is the point of communication between the motor neuron and the skeletal muscle cell, and it is the site for the transmission of action potential to activate contraction. The integrity of the NMJ is perturbed in neuromuscular disorders and in skeletal muscle aging and disuse [20,[28][29][30], with a consequent loss of its organization, fragmentation and degeneration, contributing to reduced muscle performance. Already in 2006, Lagouge and collaborators [7], based on the evidence that RES improved the motor coordination and traction force in mice fed on a high-fat diet, suggested that RES could modulate neuromuscular communication. ...
Resveratrol is a natural polyphenol utilized in Chinese traditional medicine and thought to be one of the determinants of the “French Paradox”. More recently, some groups evidenced its properties as a calorie-restriction mimetic, suggesting that its action passes through the modulation of skeletal muscle metabolism. Accordingly, the number of studies reporting the beneficial effects of resveratrol on skeletal muscle form and function, in both experimental models and humans, is steadily increasing. Although studies on animal models confer to resveratrol a good potential to ameliorate skeletal muscle structure, function and performance, clinical trials still do not provide clear-cut information. Here, we first summarize the effects of resveratrol on the distinct components of the skeletal muscle, such as myofibers, the neuromuscular junction, tendons, connective sheaths and the capillary bed. Second, we review clinical trials focused on the analysis of skeletal muscle parameters. We suggest that the heterogeneity in the response to resveratrol in humans could depend on sample characteristics, treatment modalities and parameters analyzed; as well, this heterogeneity could possibly reside in the complexity of skeletal muscle physiology. A systematic programming of treatment protocols and analyses could be helpful to obtain consistent results in clinical trials involving resveratrol administration.
... The skeletal muscle comprises terminally differentiated multinuclear muscle cells (myofibers), and populations of mononuclear cells including myogenic SCs and nonmyogenic "accessory" cells, e.g., FAPs, fibroblasts, adipocytes, and innate and adaptive immune cells [20,21]. Loss of muscle mass and strength, increased infiltration of fat and fibrotic tissue, as well as deterioration of neuromuscular junctions (NMJs) and local circulation are predominant features of skeletal muscle aging [22][23][24]. Myogenic and nonmyogenic stem/progenitor cells and innate immune cells play a critical role in skeletal muscle regeneration and aging. In this section, we discuss the involvement of SCs and FAPs in skeletal muscle aging; we will separately discuss the function of macrophages, the predominant innate immune cell population in skeletal muscle, in Sections 3-9 below. ...
... Skeletal muscle contracts voluntarily by motoneurons and the NMJ is the structure that converts the excitation signal to contraction force. In the NMJ, presynaptic nerve endings packed with acetylcholine (Ach) connect to postsynaptic endplates enriched with Ach receptors (AchR) [23,137]. During aging, there is marked deterioration of the NMJ structure and function, along with increased presynaptic nerve branching and reduced neurotransmitter vesicles [23,137,138], and thinner postsynaptic endplates with less AchRs, especially in type II myofibers [23,137,138]. ...
... In the NMJ, presynaptic nerve endings packed with acetylcholine (Ach) connect to postsynaptic endplates enriched with Ach receptors (AchR) [23,137]. During aging, there is marked deterioration of the NMJ structure and function, along with increased presynaptic nerve branching and reduced neurotransmitter vesicles [23,137,138], and thinner postsynaptic endplates with less AchRs, especially in type II myofibers [23,137,138]. These aging-related changes promote myofiber denervation, reduce fiber size, and increase hybrid fibers. ...
The skeletal muscle is a dynamic organ composed of contractile muscle fibers, connective tissues, blood vessels and nerve endings. Its main function is to provide motility to the body, but it is also deeply involved in systemic metabolism and thermoregulation. The skeletal muscle frequently encounters microinjury or trauma, which is primarily repaired by the coordinated actions of muscle stem cells (satellite cells, SCs), fibro-adipogenic progenitors (FAPs), and multiple immune cells, particularly macrophages. During aging, however, the capacity of skeletal muscle to repair and regenerate declines, likely contributing to sarcopenia, an age-related condition defined as loss of muscle mass and function. Recent studies have shown that resident macrophages in skeletal muscle are highly heterogeneous, and their phenotypes shift during aging, which may exacerbate skeletal muscle deterioration and inefficient regeneration. In this review, we highlight recent insight into the heterogeneity and functional roles of macrophages in skeletal muscle regeneration, particularly as it declines with aging.
... Decline in neuromuscular function with aging is known to be a major determinant of disability and all-cause mortality in late life (Ferrucci et al., 2012;Gonzalez-Freire et al., 2014;Guralnik et al., 1994Guralnik et al., , 1995Newman et al., 2006;Sabia et al., 2014;Studenski et al., 2011;Vazzana et al., 2010). Despite the importance of the problem, the neurobiology of age-associated muscle atrophy and weakness, termed sarcopenia, is poorly understood. ...
Decline in neuromuscular function with aging is known to be a major determinant of disability and all-cause mortality in late life. Despite the importance of the problem, the neurobiology of age-associated muscle weakness is poorly understood. In a previous report, we performed untargeted metabolomics on frail older adults and discovered prominent alteration in the kynurenine pathway, the major route of dietary tryptophan degradation that produces neurotoxic intermediate metabolites. We also showed that neurotoxic kynurenine pathway metabolites are correlated with increased frailty score. For the present study, we sought to further examine the neurobiology of these neurotoxic intermediates by utilizing a mouse model that has a deletion of the quinolinate phosphoribosyltransferase (QPRT) gene, a rate-limiting step of the kynurenine pathway. QPRT-/- mice have elevated neurotoxic quinolinic acid level in the nervous system throughout their lifespan. We found that QPRT-/- mice have accelerated declines in neuromuscular function in an age- and sex-specific manner compared to control strains. In addition, the QPRT-/- mice show premature signs of frailty and body composition changes that are typical for metabolic syndrome. Our findings suggest that the kynurenine pathway may play an important role in frailty and age-associated muscle weakness.
... Neuromuscular junctions (NMJs), while showing the structural features of other chemical synapses, act as a bridge between the nervous (motor neuron) and skeletal muscle (myofiber) systems. NMJs play a relevant role in age-related musculoskeletal impairment [29,30]. Whether NMJ changes trigger or follow the age-associated decline of muscle mass and strength is unsolved. ...
Declines in physical performance and cognition are commonly observed in older adults. The geroscience paradigm posits that a set of processes and pathways shared among age-associated conditions may also serve as a molecular explanation for the complex pathophysiology of physical frailty, sarcopenia, and cognitive decline. Mitochondrial dysfunction, inflammation, metabolic alterations, declines in cellular stemness, and altered intracellular signaling have been observed in muscle aging. Neurological factors have also been included among the determinants of sarcopenia. Neuromuscular junctions (NMJs) are synapses bridging nervous and skeletal muscle systems with a relevant role in age-related musculoskeletal derangement. Patterns of circulating metabolic and neurotrophic factors have been associated with physical frailty and sarcopenia. These factors are mostly related to disarrangements in protein-to-energy conversion as well as reduced calorie and protein intake to sustain muscle mass. A link between sarcopenia and cognitive decline in older adults has also been described with a possible role for muscle-derived mediators (i.e., myokines) in mediating muscle-brain crosstalk. Herein, we discuss the main molecular mechanisms and factors involved in the muscle-brain axis and their possible implication in cognitive decline in older adults. An overview of current behavioral strategies that allegedly act on the muscle-brain axis is also provided.
... Elderly individuals suffer a progressive loss of muscle mass and strength (sarcopenia) and motor function [37][38][39][40][41] . However, the motor deficit in middle-aged mice is less likely to be due to motor neuron loss, NMJ denervation, or muscle atrophy. ...
Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15–18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.
... We also assessed the status of NMJ in response to NT-3 gene therapy in this model as there is evidence that changes in endplate morphology and NMJ remodeling occur with aging and precede loss of fast motor units [20]. Using immunohistochemistry-based parameters [11], we analyzed a total of 330 NMJs derived from intrinsic foot muscles of NT-3 treated and untreated aged C57BL/6 mice. ...
Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway. We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia, via intramuscular injection 1 × 1011 vg AAV1.tMCK.NT-3, at 18 months of age. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle. AAV1.NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.
