Loss of neuromuscular junction integrity and muscle atrophy in skeletal muscle disuse

Sirago, Giuseppe; Pellegrino, Maria Antonietta; Bottinelli, Roberto; Franchi, Martino V.; Narici, Marco V.

doi:10.1016/j.arr.2022.101810

Cited by 17 publications

(12 citation statements)

References 147 publications

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“…When disuse is prolonged, NMJ instability may contribute to the activation of the atrophic program [ 3 , 4 , 5 , 6 ]. Thus, a better understanding of the causes and players involved in NMJ instability may clarify the pathophysiological processes underlying disuse atrophy [ 39 ]. In this ULLS experiment, evidence of NMJ instability and axonal damage was suggested by the increased serum concentrations of CAF and NfL in response to 10 days of unloading, as recently reported by our group in the same cohort [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Sarcolemmal Hemichannels and Inflammatory Transcripts with Neuromuscular Junction Instability during Lower Limb Unloading in Humans

Sirago

Candia

Franchi

et al. 2023

Biology

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Human skeletal muscle atrophy and a disproportionate force loss occur within a few days of unloading in space and on Earth, but the underlying mechanisms are not fully understood. Disruption of neuromuscular junction homeostasis has been proposed as one of the possible causes. Here, we investigated the potential mechanisms involved in this neuromuscular disruption induced by a 10-day unilateral lower limb suspension (ULLS) in humans. Specifically, we investigated hemichannels’ upregulation, neuromuscular junction and axonal damage, neurotrophins’ receptor downregulation and inflammatory transcriptional signatures. Biomarkers were evaluated at local and systemic levels. At the sarcolemmal level, changes were found to be associated with an increased expression of connexin 43 and pannexin-1. Upregulation of the inflammatory transcripts revealed by deep transcriptomics was found after 10 days of ULLS. The destabilisation of the neuromuscular junction was not accompanied by changes in the secretion of the brain-derived neurotrophic factor and neurotrophin-4, while their receptor, BDNF/NT growth factors receptor (TrkB), decreased. Furthermore, at 5 days of ULLS, there was already a significant upregulation of the serum neurofilament light chain concentration, an established clinical biomarker of axonal injury. At 10 days of ULLS, other biomarkers of early denervation processes appeared. Hence, short periods of muscle unloading induce sarcolemmal hemichannels upregulation, inflammatory transcripts upregulation, neuromuscular junction instability and axonal damage.

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Section: Discussionmentioning

confidence: 99%

Upregulation of Sarcolemmal Hemichannels and Inflammatory Transcripts with Neuromuscular Junction Instability during Lower Limb Unloading in Humans

Sirago

Candia

Franchi

et al. 2023

Biology

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

Section: Nmj Abnormalities Affect Mitochondrial Functionmentioning

confidence: 99%

“…At present, the exact pathogenesis of sarcopenia remains unclear. 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 ; Stephenson et al., 2023 ; Xiao et al., 2020 ) in individuals with sarcopenia. 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 ).…”

Section: Introductionmentioning

confidence: 99%

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

Miao,

Xie,

Song

et al. 2024

Physiological Reports

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Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age‐associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit‐acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia.

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“…44 Disruptions to NMJ structure and stability, such as denervation (i.e., loss of the presynaptic terminal), in multiple pathological conditions (e.g., neurological disorders, nerve injury, VML, and chronic disuse) lead to muscle atrophy and loss of function. [44][45][46][47][48] Conversely, the extent of re-establishment of NMJs after peripheral nerve injury has a strong positive correlation with functional recovery. 46 Reinnervation is of particular importance in VML due to the secondary denervation of muscle fibers that follows the primary loss of nerves and NMJs at the time of injury, which results in significant denervation of NMJs by 48 days post-injury and further functional decline.…”

Section: Introductionmentioning

confidence: 99%

Cell-scale porosity in microporous annealed particle (MAP) scaffolds modulates immune response and promotes formation of innervated muscle fibers in volumetric muscle loss injuries

Ayala,

Christ,

Griffin

2024

Preprint

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Volumetric muscle loss (VML) is caused by severe traumatic injuries to skeletal muscle and is characterized by the irreversible loss of contractile tissue and permanent functional deficits. VML injuries cannot be healed by endogenous mechanisms and are exceptionally difficult to treat in the clinic due to the excessive upregulation of the inflammatory response, which leads to fibrosis, denervation of muscle fibers, and impaired regeneration. These injuries lead to long-term disability. Using a rodent model of VML in the tibialis anterior, this study presents microporous annealed particle (MAP) hydrogel scaffolds as a biomaterial platform for improved muscle regeneration in VML injuries, specifically highlighting the benefits of cell-scale porosity. In contrast to bulk (i.e., nanoporous) hydrogel scaffolds, MAP scaffolds promote integration by avoiding the foreign body response, decreasing the rate of implant degradation, and shifting macrophage polarization to favor regeneration. In addition, cell migration and angiogenesis throughout the implant precede the degradation of MAP scaffolds, including the formation of muscle fibers and neuromuscular junctions within MAP scaffolds prior to degradation. These fibers and junctions continue to develop as the implant degrades, indicating that MAP hydrogel scaffolds are a promising therapeutic approach for VML injuries.

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Loss of neuromuscular junction integrity and muscle atrophy in skeletal muscle disuse

Cited by 17 publications

References 147 publications

Upregulation of Sarcolemmal Hemichannels and Inflammatory Transcripts with Neuromuscular Junction Instability during Lower Limb Unloading in Humans

Upregulation of Sarcolemmal Hemichannels and Inflammatory Transcripts with Neuromuscular Junction Instability during Lower Limb Unloading in Humans

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

Cell-scale porosity in microporous annealed particle (MAP) scaffolds modulates immune response and promotes formation of innervated muscle fibers in volumetric muscle loss injuries

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