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.

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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... It is important to remark that an altered NMJ functionality can be found in several pathologies, such as aging, acute denervation, Duchenne Muscular Dystrophy (DMD) and Amyotrophic Lateral sclerosis (ALS). 5,10,13,24 In particular, ALS is the most frequent neurodegenerative disease where the progressive failure of the neuromuscular system results in weakness and atrophy of the limb muscle, gradual paralysis and death from respiratory failure. 5,21 Among all the animal models used to study ALS, SOD1 G93A mouse is one of the most employed 12 and it is based on the expression of the human SOD1 protein containing the G93A mutation. ...
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Introduction The neuromuscular junction (NMJ) is a chemical synapse responsible for converting electrical pulses generated by the motor neuron into electrical activity in muscle fibers, and is severely impaired in various diseases, such as Amyotrophic Lateral Sclerosis (ALS). Here, we proposed a novel technique to measure, for the first time, NMJ functionality in isotonic conditions, which better reflect muscle physiological activity. Methods We employed the in-situ testing technique, studied a proper placing of two pairs of wire electrodes for nerve and muscle stimulation, developed an extensive testing protocol, and proposed a novel parameter, the Isotonic Neurotransmission Failure (INF), to properly capture the impairments in neurotransmission during isotonic fatigue. We employed wild-type mice to assess the feasibility of the proposed technique, and the ALS model SOD1 G93A mice to demonstrate the validity of the INF . Results Results confirmed the measurement accuracy in term of average value and coefficient of variation of the parameters measured through nerve stimulation in comparison with the corresponding values obtained for membrane stimulation. The INF values computed for the SOD1 G93A tibialis anterior muscles pointed out an impairment of ALS mice during the isotonic fatigue test, whereas, as expected, their resistance to fatigue was higher. Conclusions In this work we devised a novel technique and a new parameter for a deep assessment of NMJ functionality in isotonic conditions, including fatigue, which is the most crucial condition for the neuronal signal transmission. This technique may be applied to other animal models, to unravel the mechanisms behind muscle-nerve impairments in other neurodegenerative pathologies.
... Aging can induce the loss of the protective functions of FoxOs, which in mammals, can exert their protective effects through the regulation of superoxide dismutases (SODs) and have roles in the regulation of GSHmediated detoxification by inducing the transcription of GSTM1 [13,35]. When considering neuromuscular function specifically, aging may increase oxidative stress in motor neurons [11]. Preliminary analysis of liver proteins by our group has revealed that both GSTM1 and SOD2 are increased with aging (unpublished observations), which may be reflecting the degree of oxidative stress in the local environment [16]. ...
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... This agerelated decline in neuromuscular mass and function is referred to as "sarcopenia" [6], which first manifests at about 50 years of age, while its rate of degeneration noticeably accelerates beyond the age of 60 years [7,8]. In recent years, the NMJ has increasingly been linked to the onset and progression of sarcopenia [9][10][11]. Although it is unlikely that aging of the NMJ alone is the causative factor of sarcopenia, it is just as unlikely that it has no effect on age-related loss of neuromuscular function. ...
... Moreover, the complexity of this branching-with essentially, the total branch length as a factor of the branch number (please see figure legend for details)-has been found to be greater among aged nerve terminals than young ones [47][48][49][50]. It has been suggested that this indicates greater remodeling of the motor neuron in an attempt to improve communication between pre-and postsynaptic components of the NMJ, as such communication is pared down with aging [9,51]. ...
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... Both can happen independently, despite having a possible synergic action and age plays a role in aggravating this scenario (15). Sarcopenia may result from a combination of these deleterious alterations, or still, by other muscle morphology and function disruptive modifications, such as loss of innervation, among other (16,17). ...
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... Overall, the selective motor neuron expression of Stmn2 that we observed in the ventral horn would seem to suggest that these phenotypes arise because of motor neuron autonomous dysfunction of the motor axon. This observation would in turn be consistent with the notion that axonal dysfunction and NMJ denervation leads to a set of classical signs of degeneration of the muscle, which are also observed following other denervating injuries (Cappello and Francolini, 2017;Gonzalez-Freire et al., 2014). Thus, when we eliminated the mouse homolog of one prominent RNA target of TDP43, STMN2, we found that it was, in and of itself, sufficient to induce motor neuropathy, a primary contributor to the spreading paralysis that occurs in patients with ALS. ...
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... It has been largely demonstrated that a wrong nutrition and a sedentary lifestyle are linked to a high incidence of chronic metabolic diseases such as cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), cancer and osteoporosis [1], while exercise plays a fundamental role in preventing and treating these pathologies [2]. Interestingly, the healthpromoting actions of exercise are mediated by metabolic and immune effects that involve several mechanisms, such as the promotion of an anti-inflammatory state, activation of the hypothalamic-pituitary-adrenal (HPA) axis, augmentation of synaptic plasticity and reinforcement of neuromuscular function [3,4]. Moreover, skeletal muscle acts like an endocrine organ by producing a multitude of hormones and cytokines in response to muscle contraction, which exert their impacts on several organs and tissues [5]. ...
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Purpose: Pathological and age-related declines in both physical fitness and muscle function are well established; however, the role mitochondrial function plays in these changes is less understood. With low skeletal muscle mass and function associated with poorer surgical outcomes, treatments and interventions that can limit the decrease in muscle mass and function seen in the elderly, known as sarcopenia, and in those with cancer, known as cancer cachexia, is vital. Methods: A systematic review and meta-analysis was conducted to determine the impact of sarcopenia on overall and disease-free survival in patients with locally advanced rectal cancer. In addition, young and older healthy volunteers were recruited to determine links between advancing age and declines in global physical fitness and muscle function, as well as investigate if similar declines in mitochondrial function occur. Results: Our systematic review and meta-analysis established that pre-existing sarcopenia was associated with shorter overall and disease-free survival in patients with locally advanced rectal cancer. Within our healthy volunteer cohort, age significantly impacted global physical function (HGS, 1-RM and VO2max) and measures of muscle architecture, with reduced status in older adults. Conversely, mitochondrial function was not different between the age-groups. Conclusions: There is clearly an age-related decline in global physical fitness and muscle function, however it remains unknown to what degree mitochondrial function is implicated in these changes. With sarcopenia and cachexia both having a negative impact on various prognostic outcomes, interventions such as exercise training regimes show promising results in improving cardiovascular fitness and muscle mass/ function in both elderly and cancer patients undergoing surgery. Despite this, if or how these interventions may modify any mitochondrial dysfunction that may exist, especially in cancer patients undergoing neoadjuvant treatment prior to surgery is wholly unknown. More research is required to understand the complex relationship between mitochondrial function and the changes seen in the skeletal muscle of both the elderly and cancer patients.