Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction

“In contrast, secondary sarcopenia is associated with various diseases (Figure 1) (Bauer et al., 2019; Chen et al., 2020; Nishikawa et al., 2016), such as intensive care unit-acquired weakness (ICU-AW), amyotrophic lateral sclerosis (ALS), and muscular atrophy due to inadequate exercise and…”

“Sarcopenia, a progressive and systemic skeletal muscle disease (Cruz-Jentoft & Sayer, 2019; Dent et al., 2018), is categorized into primary and secondary types.”

“Mitochondria are highly dynamic organelles with the capacity to modify their function through various mechanisms, including changes in mitochondrial DNA (mtDNA), fusion or fission (Westermann, 2010), and auto-phagy.”

“…have multiple functions, including adenosine triphosphate (ATP) production (Altman et al., 2019), neurotransmitter release (Misgeld & Schwarz, 2017), calcium regulation (Wu, Zheng, et al., 2021), signaling (Ly & Verstreken, 2006), and amino acid and lipid metabolism (Spinelli & Haigis, 2018).”

“The NMJ, the contact point between the motor neuron axon and skeletal muscle, is composed of motor nerve endings, perisynaptic Schwann cells, and skeletal muscle fibers (Court et al., 2008; Li et al., 2018; Sanes & Lichtman, 1999).”

“…swelling and SOCS3 upregulation NMJ deterioration Bannow et al. (2022) the study also found that mitochondrial function within the muscle decreased during aging, as well as in response to altered neuronal redox status prior to NMJ deterioration or loss of muscle mass and force (Zorov et al., 2000).”

“Mitochondrial fusion proteins 1 and 2 and optic atrophy 1, along with fission proteins such as dynamin-related protein 1, mitochondrial fission factor, and fission protein 1 (Detmer & Chan, 2007), are critical for maintaining mitochondrial function (Archer et al., 2013).”

“…proteins 1 and 2 in skeletal muscle can lead to mtDNA deficiency and the accumulation of small muscle sizes (Chen et al., 2010); moreover, mitochondrial autophagy, which facilitates the removal of dysfunctional mitochondria, is essential for the maintenance of muscle mass (Masiero et al., 2009).”

“…by knock-out of mitochondrial fusion proteins 1 and 2 in skeletal muscle can lead to mtDNA deficiency and the accumulation of small muscle sizes (Chen et al., 2010); moreover, mitochondrial autophagy, which facilitates the removal of dysfunctional mitochondria, is essential for the maintenance…”

“Mitochondrial fusion proteins 1 and 2 and optic atrophy 1, along with fission proteins such as dynamin-related protein 1, mitochondrial fission factor, and fission protein 1 (Detmer & Chan, 2007), are critical for maintaining mitochondrial function (Archer et al., 2013).”

“In contrast, secondary sarcopenia is associated with various diseases (Figure 1) (Bauer et al., 2019; Chen et al., 2020; Nishikawa et al., 2016), such as intensive care unit-acquired weakness (ICU-AW), amyotrophic lateral sclerosis (ALS), and muscular atrophy due to inadequate exercise and…”

“In contrast, secondary sarcopenia is associated with various diseases (Figure 1) (Bauer et al., 2019; Chen et al., 2020; Nishikawa et al., 2016), such as intensive care unit-acquired weakness (ICU-AW), amyotrophic lateral sclerosis (ALS), and muscular atrophy due to inadequate exercise and…”

“Primary sarcopenia is age-associated and has become one of the major health problems in older adults (Gustafsson & Ulfhake, 2021; Papadopoulou, 2020), leading to an increased risk of falls, disability, and mortality (Senior et al., 2015; Westbury et al., 2023).”

“While only approximately 50% of active synapses in the central nervous system of adult rodents contain mitochondria, NMJs are notably enriched in tightly packed mitochondrial networks (Altman et al., 2019; Misgeld & Schwarz, 2017).”

“…aging affects the structure and physiological functions of the NMJs, leading to NMJ fragmentation (Kurokawa et al., 1999; Pratt et al., 2021; Valdez et al., 2010), axon remodeling (Smith & Rosenheimer, 1982), reduction of presynaptic vesicles and nerve endings (Rosenheimer, 1990), decreases…”

“…numerous studies highlighting the significant roles of the NMJs and mitochondria in sarcopenia, only two interventions have been currently reported to effectively manage NMJs and mitochondrial disruption in sarcopenia: exercise and calorie restriction (CR) (Jang et al., 2012; Shen et al., 2023).”

“At present, regular exercise (Carol & Hodgson, 2022; Collao et al., 2023; Jacob et al., 2023) a ketogenic diet (Goossens et al., 2019; Yakupova et al., 2022), and a calorie-restricted diet (Faulks et al., 2006; Jang et al., 2012) FIGURE 3 Sarcopenia.”

“This approach is gaining interest because a ketogenic diet or in vitro ketogenic supplementation with ketone bodies can increase mitochondrial activity in young animals and improve mitochondrial mass and function in older animals (Cioni et al., 2019).”

“In healthy adult animals, local protein synthesis occurs in the axons and synapses of NMJs (Hafner et al., 2019), playing an important role in the structural and functional integrity of mitochondria.”

“Additionally, another study suggests that mitochondrial dysfunction and oxidative stress might directly affect myosin interaction and force generation but do not significantly affect the stability of the NMJs (Carnio et al., 2014).”

“Moreover, in patients with ICU-AW, inflammation, hyperglycemia, and free radicals exacerbate mitochondrial damage, leading to impaired oxygen utilization in mitochondria and thereby affecting NMJ function (Friedrich et al., 2015).”

“The NMJ, the contact point between the motor neuron axon and skeletal muscle, is composed of motor nerve endings, perisynaptic Schwann cells, and skeletal muscle fibers (Court et al., 2008; Li et al., 2018; Sanes & Lichtman, 1999).”

“Recent studies have increasingly demonstrated that NMJ instability is closely related to the occurrence and development of sarcopenia (Ang et al., 2022; Gonzalez-Freire et al., 2014; Monti et al., 2021).”

“In primary sarcopenia, age-related point mutations in mtDNA are a contributing factor (Wallace, 2013).”

“These findings suggest that impairments in the NMJs and mitochondrial function could be potential contributing factors to the development of sarcopenia (Ahn et al., 2019; Jang et al., 2010).”

“In addition, CR enhances the expression of genes involved in ROS scavenging and alters the fatty acid composition of mitochondrial membranes, thereby reducing lipid oxidation and proton leakage (Drew et al., 2003; Short et al., 2005).”

“…even describe sarcopenia as a “disorder of the NMJs.” ( Alchin, 2014; Gatti et al., 2023) Moreover, mitochondria, which are enriched on both sides of the NMJs (Lee & Peng, 2006; Vos et al., 2010), play an important role in maintaining NMJ stability and transmission (Martinez-Pena et al., 2021).”

“Cachexia, a systemic wasting condition, is typically considered a late-stage manifestation of chronic diseases, such as cancer, organ failure, or infections (Ferrer et al., 2023).”

“…(ICU-AW), amyotrophic lateral sclerosis (ALS), and muscular atrophy due to inadequate exercise and nutrition, and often results in prolonged hospital stays and higher mortality rates (Cacciani et al., 2020; Mitobe et al., 2019; Riancho et al., 2021; Schweickert et al., 2022; Wieske et al., 2015).”

“…have multiple functions, including adenosine triphosphate (ATP) production (Altman et al., 2019), neurotransmitter release (Misgeld & Schwarz, 2017), calcium regulation (Wu, Zheng, et al., 2021), signaling (Ly & Verstreken, 2006), and amino acid and lipid metabolism (Spinelli & Haigis, 2018).”

“…of the neuromuscular junction (NMJ) (Carnio et al., 2014; Iyer et al., 2021; Shi et al., 2014; Sirago et al., 2023) and changes in mitochondrial function (Baraldo et al., 2020; Dupuis et al., 2009; Spendiff et al., 2016; Stephenson et al., 2023; Xiao et al., 2020) in individuals with sarcopenia.”

“Primary sarcopenia is age-associated and has become one of the major health problems in older adults (Gustafsson & Ulfhake, 2021; Papadopoulou, 2020), leading to an increased risk of falls, disability, and mortality (Senior et al., 2015; Westbury et al., 2023).”

“Moreover, regulation of the mitochondrial network plays a key role in determining muscle size (Herbst et al., 2007; Rahman & Quadrilatero, 2021; Romanello & Sandri, 2021; Xu et al., 2022).”

“Moreover, regulation of the mitochondrial network plays a key role in determining muscle size (Herbst et al., 2007; Rahman & Quadrilatero, 2021; Romanello & Sandri, 2021; Xu et al., 2022).”

“…of the NMJs can lead to muscle weakness or even paralysis (Lepore et al., 2019; Ohkawara et al., 2021; So et al., 2018), NMJ instability is considered to be an initiating and driving factor of the pathology of sarcopenia (Deschenes et al., 2010; Dobrowolny et al., 2021; Rodrigues et al., 2018).”

“Mitochondrial dysfunction is increasingly recognized as a critical contributor to NMJ instability, which leads to skeletal muscle atrophy (Anagnostou & Hepple, 2020; O'Connor et al., 2023; Kim et al., 2023; Rygiel et al., 2016).”

“This finding supports the view that the pathological changes of mitochondria precede NMJ alterations, affecting both the structure and function of the NMJs (Dobrowolny et al., 2018; Pollari et al., 2014).”

“Interestingly, the clearance of axonal TDP-43 increases the level of nuclear-encoded mitochondrial proteins in axons and synapses (Altman et al., 2021).”

“For example, multiple or single deletions of mtDNA can lead to alterations in myelin sheaths and crystal-like inclusions in Schwann cells at NMJs (Pareyson et al., 2013).”

“Taken together, the aforementioned evidence suggests a close relationship between mitochondria and the NMJs (Lee & Peng, 2008; Rikhy et al., 2007; Wilson et al., 2018).”

“…have multiple functions, including adenosine triphosphate (ATP) production (Altman et al., 2019), neurotransmitter release (Misgeld & Schwarz, 2017), calcium regulation (Wu, Zheng, et al., 2021), signaling (Ly & Verstreken, 2006), and amino acid and lipid metabolism (Spinelli & Haigis, 2018).”

“Recent studies have increasingly demonstrated that NMJ instability is closely related to the occurrence and development of sarcopenia (Ang et al., 2022; Gonzalez-Freire et al., 2014; Monti et al., 2021).”

“Nevertheless, some studies have found abnormalities in the morphology of the neuromuscular junction (NMJ) (Carnio et al., 2014; Iyer et al., 2021; Shi et al., 2014; Sirago et al., 2023) and changes in mitochondrial function (Baraldo et al., 2020; Dupuis et al., 2009; Spendiff et al., 2016;…”

“Another promising strategy involves the administration of ketone bodies or the activation of ketogenesis (Goossens et al., 2019; Yakupova et al., 2022).”

“…axon remodeling (Smith & Rosenheimer, 1982), reduction of presynaptic vesicles and nerve endings (Rosenheimer, 1990), decreases in both the number (Courtney & Steinbach, 1981) and affinity (Moreira-Pais et al., 2022; Smith & Chapman, 1987) of acetylcholine receptors (AChRs), and changes in…”

“At present, regular exercise (Carol & Hodgson, 2022; Collao et al., 2023; Jacob et al., 2023) a ketogenic diet (Goossens et al., 2019; Yakupova et al., 2022), and a calorie-restricted diet (Faulks et al., 2006; Jang et al., 2012) FIGURE 3 Sarcopenia.”

“…the p.Ser59Leu variant in the mitochondrial protein CHCHD10, which were used to model mitochondrial myopathy with unstable mtDNA, showed mitochondrial changes in skeletal muscles before NMJ instability, motor neuron degeneration, and high fragmentation of the motor endplate (Genin et al., 2019).”

“Exercise improves mitochondrial function and NMJ health (Kim et al., 2013; Lee et al., 2019).”

“…of the NMJs can lead to muscle weakness or even paralysis (Lepore et al., 2019; Ohkawara et al., 2021; So et al., 2018), NMJ instability is considered to be an initiating and driving factor of the pathology of sarcopenia (Deschenes et al., 2010; Dobrowolny et al., 2021; Rodrigues et al., 2018).”

“Both presynaptic nerve endings and postsynaptic end-plate regions are rich in mitochondria (Anagnostou & Hepple, 2020; Lepore et al., 2019; Spendiff et al., 2016), which provide a large amount of ATP for neuromuscular transmission.”

“…numerous studies highlighting the significant roles of the NMJs and mitochondria in sarcopenia, only two interventions have been currently reported to effectively manage NMJs and mitochondrial disruption in sarcopenia: exercise and calorie restriction (CR) (Jang et al., 2012; Shen et al., 2023).”

“For example, a study of transgenic mice overexpressing fused in sarcoma (FUS), a marker of pathologies in FUS-related ALS and frontotemporal dementia, showed that mitochondrial defects preceded NMJ instability (So et al., 2018).”

“Both presynaptic nerve endings and postsynaptic end-plate regions are rich in mitochondria (Anagnostou & Hepple, 2020; Lepore et al., 2019; Spendiff et al., 2016), which provide a large amount of ATP for neuromuscular transmission.”

“Primary sarcopenia is age-associated and has become one of the major health problems in older adults (Gustafsson & Ulfhake, 2021; Papadopoulou, 2020), leading to an increased risk of falls, disability, and mortality (Senior et al., 2015; Westbury et al., 2023).”

“…normal biological capacity could be produced in the nervous system, and the flies could survive in the presence of a small number of mitochondria; (Trevisan et al., 2018) this finding suggests that these mitochondrial fragments are functional, and a small number of mitochondria with bioenergetic…”

“Moreover, regulation of the mitochondrial network plays a key role in determining muscle size (Herbst et al., 2007; Rahman & Quadrilatero, 2021; Romanello & Sandri, 2021; Xu et al., 2022).”

“Both presynaptic nerve endings and postsynaptic end-plate regions are rich in mitochondria (Anagnostou & Hepple, 2020; Lepore et al., 2019; Spendiff et al., 2016), which provide a large amount of ATP for neuromuscular transmission.”

“This finding supports mitochondrial hydrogen peroxide as an important effector in NMJ changes associated with sarcopenia (Xu et al., 2021).”

“…physiological functions of the NMJs, leading to NMJ fragmentation (Kurokawa et al., 1999; Pratt et al., 2021; Valdez et al., 2010), axon remodeling (Smith & Rosenheimer, 1982), reduction of presynaptic vesicles and nerve endings (Rosenheimer, 1990), decreases in both the number (Courtney &…”

“The NMJ, the contact point between the motor neuron axon and skeletal muscle, is composed of motor nerve endings, perisynaptic Schwann cells, and skeletal muscle fibers (Court et al., 2008; Li et al., 2018; Sanes & Lichtman, 1999).”

“…of the neuromuscular junction (NMJ) (Carnio et al., 2014; Iyer et al., 2021; Shi et al., 2014; Sirago et al., 2023) and changes in mitochondrial function (Baraldo et al., 2020; Dupuis et al., 2009; Spendiff et al., 2016; Stephenson et al., 2023; Xiao et al., 2020) in individuals with sarcopenia.”

“Moreover, regulation of the mitochondrial network plays a key role in determining muscle size (Herbst et al., 2007; Rahman & Quadrilatero, 2021; Romanello & Sandri, 2021; Xu et al., 2022).”

“Along with affecting energy supply, mitochondrial dysfunction increases the production of free radicals and ROS, triggering a vicious cycle of damage to macromolecules and organelles (Alizadeh Pahlavani et al., 2022; Martin et al., 2021).”

“…reduction of presynaptic vesicles and nerve endings (Rosenheimer, 1990), decreases in both the number (Courtney & Steinbach, 1981) and affinity (Moreira-Pais et al., 2022; Smith & Chapman, 1987) of acetylcholine receptors (AChRs), and changes in terminal Schwann cells, such as contraction or…”

“Primary sarcopenia is age-associated and has become one of the major health problems in older adults (Gustafsson & Ulfhake, 2021; Papadopoulou, 2020), leading to an increased risk of falls, disability, and mortality (Senior et al., 2015; Westbury et al., 2023).”

“A study showed that accumulation of mislocalized TAR- DNA-binding protein (TDP)- 43 at the NMJs, a phenomenon observed in the motor neurons of approximately 95% of ALS patients, impaired local translation of nuclear-encoded mitochondrial proteins and inhibited local protein synthesis in distal axons and NMJs, thereby…”

“Mitochondria are transported from the main biosynthetic sites in the cell body along the cytoskeleton, traveling down the axon to the synaptic terminal (Barnhart, 2016; González & Couve, 2014).”

“In primary sarcopenia, aging affects the structure and physiological functions of the NMJs, leading to NMJ fragmentation (Kurokawa et al., 1999; Pratt et al., 2021; Valdez et al., 2010), axon remodeling (Smith & Rosenheimer, 1982), reduction of presynaptic vesicles and nerve endings (Rosenheimer,…”

“Mitochondrial dysfunction is increasingly recognized as a critical contributor to NMJ instability, which leads to skeletal muscle atrophy (Anagnostou & Hepple, 2020; O'Connor et al., 2023; Kim et al., 2023; Rygiel et al., 2016).”

“This finding supports the view that the pathological changes of mitochondria precede NMJ alterations, affecting both the structure and function of the NMJs (Dobrowolny et al., 2018; Pollari et al., 2014).”

“The normal structure and function of the NMJs play important roles in mitochondrial function (Table 2) (Sirago et al., 2023).”

“Exercise improves mitochondrial function and NMJ health (Kim et al., 2013; Lee et al., 2019).”

“In primary sarcopenia, aging affects the structure and physiological functions of the NMJs, leading to NMJ fragmentation (Kurokawa et al., 1999; Pratt et al., 2021; Valdez et al., 2010), axon remodeling (Smith & Rosenheimer, 1982), reduction of presynaptic vesicles and nerve endings (Rosenheimer,…”

“Additionally, an animal study also found that mitochondrial swelling, mitochondrial cristae remodeling, and membrane rupture in motor neuron terminals were followed by functional failure of the NMJs in aging rats (García et al., 2013).”

“Nevertheless, some studies have found abnormalities in the morphology of the neuromuscular junction (NMJ) (Carnio et al., 2014; Iyer et al., 2021; Shi et al., 2014; Sirago et al., 2023) and changes in mitochondrial function (Baraldo et al., 2020; Dupuis et al., 2009; Spendiff et al., 2016;…”

“Notably, these nuclear-encoded mitochondrial genes are the most abundant mRNAs in the axonal transcriptome of human motor neuron (Maciel et al., 2018).”

“…the improvement of redox-dependent sarcopenia by mitochondrial peroxiredoxin-3 overexpression did not correspond-ingly alleviate NMJ damage (Ahn et al., 2022), possibly because other sources of ROS (i.e., nicotinamide adenine dinucleotide phosphate oxidase or cytosolic phospholipase A2)…”

“At present, regular exercise (Carol & Hodgson, 2022; Collao et al., 2023; Jacob et al., 2023) a ketogenic diet (Goossens et al., 2019; Yakupova et al., 2022), and a calorie-restricted diet (Faulks et al., 2006; Jang et al., 2012) FIGURE 3 Sarcopenia.”

“Mitochondria are present both pre-and post-synaptically at NMJs (Osborne, 1967).”

“…in the mitochondria, the production of ATP and acetylcholine and the regulation of calcium and ROS are disturbed, thus affecting NMJ transmission (Batt et al., 2017; Wu, Zhao, et al., 2021), These findings indicate that mitochondria play a unique role in maintaining NMJ function and stability.”

“…of the NMJs can lead to muscle weakness or even paralysis (Lepore et al., 2019; Ohkawara et al., 2021; So et al., 2018), NMJ instability is considered to be an initiating and driving factor of the pathology of sarcopenia (Deschenes et al., 2010; Dobrowolny et al., 2021; Rodrigues et al., 2018).”

“Another promising strategy involves the administration of ketone bodies or the activation of ketogenesis (Goossens et al., 2019; Yakupova et al., 2022).”

“…of the neuromuscular junction (NMJ) (Carnio et al., 2014; Iyer et al., 2021; Shi et al., 2014; Sirago et al., 2023) and changes in mitochondrial function (Baraldo et al., 2020; Dupuis et al., 2009; Spendiff et al., 2016; Stephenson et al., 2023; Xiao et al., 2020) in individuals with sarcopenia.”

“As impairment of the NMJs can lead to muscle weakness or even paralysis (Lepore et al., 2019; Ohkawara et al., 2021; So et al., 2018), NMJ instability is considered to be an initiating and driving factor of the pathology of sarcopenia (Deschenes et al., 2010; Dobrowolny et al., 2021; Rodrigues et…”

“…alleviate NMJ damage (Ahn et al., 2022), possibly because other sources of ROS (i.e., nicotinamide adenine dinucleotide phosphate oxidase or cytosolic phospholipase A2) located in the sarcolemma and/or associated with binding lipid hydroperoxides were involved in NMJ damage (Pharaoh et al., 2020).”

“…even describe sarcopenia as a “disorder of the NMJs.” ( Alchin, 2014; Gatti et al., 2023) Moreover, mitochondria, which are enriched on both sides of the NMJs (Lee & Peng, 2006; Vos et al., 2010), play an important role in maintaining NMJ stability and transmission (Martinez-Pena et al., 2021).”

“…even describe sarcopenia as a “disorder of the NMJs.” ( Alchin, 2014; Gatti et al., 2023) Moreover, mitochondria, which are enriched on both sides of the NMJs (Lee & Peng, 2006; Vos et al., 2010), play an important role in maintaining NMJ stability and transmission (Martinez-Pena et al., 2021).”

“In critically ill patients with ICU-AW, there is evidence of ultrastructural damage and functional impairment of mitochondria in skeletal muscles (Batt et al., 2017; Felix Klawitter, 2023; Friedrich et al., 2015).”

“Moreover, NMJ function is impaired in patients with ALS (Alhindi et al., 2022; Gulino, 2023) and myasthenia gravis (Vecchio et al., 2020).”

“…(ICU-AW), amyotrophic lateral sclerosis (ALS), and muscular atrophy due to inadequate exercise and nutrition, and often results in prolonged hospital stays and higher mortality rates (Cacciani et al., 2020; Mitobe et al., 2019; Riancho et al., 2021; Schweickert et al., 2022; Wieske et al., 2015).”

“A study directly examining the effect of chronic oxidative stress on skeletal muscle in vivo found that aged mice lacking the antioxidant enzyme copper-zinc superoxide dismutase exhibited a significant increase in mitochondrial numbers near the NMJs.”

“While only approximately 50% of active synapses in the central nervous system of adult rodents contain mitochondria, NMJs are notably enriched in tightly packed mitochondrial networks (Altman et al., 2019; Misgeld & Schwarz, 2017).”

“Moreover, NMJ function is impaired in patients with ALS (Alhindi et al., 2022; Gulino, 2023) and myasthenia gravis (Vecchio et al., 2020).”

“…in the mitochondria, the production of ATP and acetylcholine and the regulation of calcium and ROS are disturbed, thus affecting NMJ transmission (Batt et al., 2017; Wu, Zhao, et al., 2021), These findings indicate that mitochondria play a unique role in maintaining NMJ function and stability.”

“Taken together, the aforementioned evidence suggests a close relationship between mitochondria and the NMJs (Lee & Peng, 2008; Rikhy et al., 2007; Wilson et al., 2018).”

“Mitochondria are transported from the main biosynthetic sites in the cell body along the cytoskeleton, traveling down the axon to the synaptic terminal (Barnhart, 2016; González & Couve, 2014).”

“…(ICU-AW), amyotrophic lateral sclerosis (ALS), and muscular atrophy due to inadequate exercise and nutrition, and often results in prolonged hospital stays and higher mortality rates (Cacciani et al., 2020; Mitobe et al., 2019; Riancho et al., 2021; Schweickert et al., 2022; Wieske et al., 2015).”

“…vesicles and nerve endings (Rosenheimer, 1990), decreases in both the number (Courtney & Steinbach, 1981) and affinity (Moreira-Pais et al., 2022; Smith & Chapman, 1987) of acetylcholine receptors (AChRs), and changes in terminal Schwann cells, such as contraction or intrusion into the synaptic…”

“Along with affecting energy supply, mitochondrial dysfunction increases the production of free radicals and ROS, triggering a vicious cycle of damage to macromolecules and organelles (Alizadeh Pahlavani et al., 2022; Martin et al., 2021).”

“Recent studies have increasingly demonstrated that NMJ instability is closely related to the occurrence and development of sarcopenia (Ang et al., 2022; Gonzalez-Freire et al., 2014; Monti et al., 2021).”

“…1999; Pratt et al., 2021; Valdez et al., 2010), axon remodeling (Smith & Rosenheimer, 1982), reduction of presynaptic vesicles and nerve endings (Rosenheimer, 1990), decreases in both the number (Courtney & Steinbach, 1981) and affinity (Moreira-Pais et al., 2022; Smith & Chapman, 1987) of…”

“…in both the number (Courtney & Steinbach, 1981) and affinity (Moreira-Pais et al., 2022; Smith & Chapman, 1987) of acetylcholine receptors (AChRs), and changes in terminal Schwann cells, such as contraction or intrusion into the synaptic cleft (Rahiminezhad et al., 2023; Wang et al., 2007).”

“Taken together, the aforementioned evidence suggests a close relationship between mitochondria and the NMJs (Lee & Peng, 2008; Rikhy et al., 2007; Wilson et al., 2018).”

“…(ICU-AW), amyotrophic lateral sclerosis (ALS), and muscular atrophy due to inadequate exercise and nutrition, and often results in prolonged hospital stays and higher mortality rates (Cacciani et al., 2020; Mitobe et al., 2019; Riancho et al., 2021; Schweickert et al., 2022; Wieske et al., 2015).”

“Additionally, in patients with chronic progressive external ophthalmoplegia, NMJ abnormalities in the extraocular muscles lead to increased neuromuscular jitter (Zou & Pan, 2022).”

“…in both the number (Courtney & Steinbach, 1981) and affinity (Moreira-Pais et al., 2022; Smith & Chapman, 1987) of acetylcholine receptors (AChRs), and changes in terminal Schwann cells, such as contraction or intrusion into the synaptic cleft (Rahiminezhad et al., 2023; Wang et al., 2007).”

“At present, regular exercise (Carol & Hodgson, 2022; Collao et al., 2023; Jacob et al., 2023) a ketogenic diet (Goossens et al., 2019; Yakupova et al., 2022), and a calorie-restricted diet (Faulks et al., 2006; Jang et al., 2012) FIGURE 3 Sarcopenia.”

“These structural changes in skeletal muscle mitochondria both in critically ill patients and aging rats may affect the function of the NMJs (Brischigliaro et al., 2023).”

“Mitochondrial swelling and SOCS3 upregulation NMJ deterioration Bannow et al. (2022) the study also found that mitochondrial function within the muscle decreased during aging, as well as in response to altered neuronal redox status prior to NMJ deterioration or loss of muscle mass and force (Zorov…”

“…resulting from mitochondrial myopathy have decreased synaptic vesicles at the presynaptic side, abnormal mitochondria aggregation at both the presynaptic and postsynaptic sides, and decreased NMJs (Lu et al., 2019), indicating the presence of pathological changes at the NMJs in sarcopenia.”

“…of the neuromuscular junction (NMJ) (Carnio et al., 2014; Iyer et al., 2021; Shi et al., 2014; Sirago et al., 2023) and changes in mitochondrial function (Baraldo et al., 2020; Dupuis et al., 2009; Spendiff et al., 2016; Stephenson et al., 2023; Xiao et al., 2020) in individuals with sarcopenia.”

“Mitochondrial dysfunction can impair stem cell activation and regeneration [20–23], while NMJ disruption may result from and exacerbate mitochondrial, inflammatory damage or muscle stem cell dysfunction [24–29].”

“…including metabolic disorders (Prasun, 2020; Moos et al., 2021), cardiovascular diseases (Peoples et al., 2019; Dai et al., 2023), neurodegenerative diseases (Golpich et al., 2017; Klemmensen et al., 2024), and neuromuscular diseases (Chaussenot and Paquis-Flucklinger, 2014; Miao et al., 2024).”

“…excess ectopic lipids are believed to induce lipotoxicity, where dysfunctional lipid metabolism promotes inflammation, oxidative injury and disruption of several cell functions, including maintenance of the neuromuscular junction (NMJ) [55–57, 64], all of which could impair neuromuscular function.”

“Furthermore, two polymorphisms within the FNDC5 promoter (rs16835198 and rs726344) are both known to impact insulin sensitivity [81], and insulin sensitivity is a contributing factor for developing sarcopenia [82,83].”

“…deterioration of NMJ includes diminished calcium sequestration by mitochondria and lower ATP production rate, contributing to impaired excitation–contraction coupling, mirroring NMJ impairments associated with ageing (Anagnostou & Hepple, 2020; Miao et al., 2024; O’Connor et al., 2023).”

“39 Therefore, the older the age, the lower the muscle strength, the lower the somatic activity function, and the poorer the dynamic control ability, which further supports the theory of postural balance.”

“Sarcopenia aggravates muscle weakness and atrophy, further impairing the function of the neuromuscular junction [40].”

“This mitochondrial dysfunction leads to the depletion of adenosine triphosphate (ATP) in muscle fibers, which may result in muscle atrophy [11,12].”

“Sarcopenia involves complex physiological and pathological interactions such as neuromuscular junction degeneration [14], mitochondrial dysfunction [15], hormonal alterations, and chronic inflammation [16].”

“…conditions, including cachexia, sarcopenia, heart failure, and type 2 diabetes, and is a significant predictor of mortality in older people (Chen et al., 2022, 2023; Gicquel et al., 2024; Jeong et al., 2024; Kim et al., 2023; Kubat et al., 2023; Landi et al., 2016; Miao et al., 2024).”

“Previous studies have highlighted NMJ dysfunction as a key contributor to muscle atrophy and motor impairments, with evidence suggesting that interventions targeting NMJ integrity can mitigate these effects [19].”

“The underlying molecular mechanisms remain unclear, but oxidative stress, chronic inflammation, and mitochondrial defects in motor neurons and muscles have been implicated in neuromuscular diseases [6,7].”

“Emerging multi-omics frameworks are beginning to better characterize this heterogeneity by identifying distinct mechanistic pathways involved in sarcopenia [20–22].”

“At the neuromuscular junction (NMJ), oxidative stress and mitochondrial dysfunction drive calcium mishandling, acetylcholine receptor fragmentation, Schwann cell inclusions, and denervation, impairing transmission and accelerating muscle atrophy [54,55].”

“84,85 The identified mitochondrial markers encompass the voltage-dependent anion-selective channel VDAC1, NADH dehydrogenase, succinate dehydrogenase, cytochrome b-c1, cytochrome c oxidase, ATP synthase subunit beta and isocitrate dehydrogenase of the outer membrane, inner membrane complexes I to V…”

“Among these, NMJ instability and dysfunction are prominent causes that could lead to muscle weakness or paralysis, and NMJ damage is likely one of the most significant pathophysiological mechanisms of sar-copenia [57, 58].”

“Neuromuscular junction (NMJ) integrity and motor unit recruitment are impaired in these conditions, leading to progressive muscle weakness and increased susceptibility to degeneration [117, 118].”

“Neuromuscular junction impairment and mitochondrial dysfunction are known causes of sarcopenia in ageing (Miao et al., 2024), however, in the present cohort, this impairment was only temporary.”

“The elevated CAF22 contributes to systemic inflammation and oxidative stress, which are known to accelerate muscle decline and impair neuromuscular integrity in aging [42 ].”

“Given that the synaptic transmission is ener-getically demanding and NMJ stability depends on mitochondrial dynamics, 39 CTRP1 may influence NMJ integrity through its role in DRP1-dependent fission.”

“Several neuromuscular disorders are linked with NMJ dysfunction and alterations in membrane function, resulting in muscle weakness [9–11], disability [12–14], and reduced quality of life [15,16].”

“Deterioration of NMJ function reduces neural input to muscles, leading to denervation-induced muscle atrophy, which is an important mechanism underlying age-related sarcopenia [39,40].”

“…convergence of canonical aging processes, including loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, epigenetic alterations, genomic instability, telomere attrition, and altered intercellular communication [ 4, 11, 18–20 ].”

“Mitochondrial dysfunction appears to contribute early to age-related NMJ vulnerability [25].”

“Sarcopenia is not merely a disorder of peripheral muscle but has been proposed as an indicator of impaired muscle-nerve interaction that may affect neuroplasticity, a key recovery mechanism after stroke [8,9].”