bims-mitrat Biomed News
on Mitochondrial transplantation and transfer
Issue of 2024–09–08
fifteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute
  1. Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
  2. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
  3. Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.
  4. Mitochondrial transfer from mesenchymal stem cells: Mechanisms and functions.
  5. Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.
  6. Effect of umbilical cord mesenchymal stem cell-derived mitochondrial transplantation on ischemia-reperfusion injury in a rat model.
  7. The platelet-mitochondria nexus in autoimmune and musculoskeletal diseases.
  8. Mitochondrial transplants to treat mitochondrial dysfunction.
  9. Frequent Icing Stimulates Skeletal Muscle Regeneration Following Injury With Necrosis in a Small Fraction of Myofibers in Rats.
  10. Skeletal muscle atrophy induces memory dysfunction via hemopexin action in healthy young mice.
  11. Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
  12. Artificial neural network inference analysis identified novel genes and gene interactions associated with skeletal muscle aging.
  13. Strenuous training combined with erythropoietin induces red cell volume expansion-mediated hypervolemia and alters systemic and skeletal muscle iron homeostasis.
  14. Human Skeletal Muscle Myoblast Culture in Aligned Bacterial Nanocellulose and Commercial Matrices.
  15. Neuromuscular impairment at different stages of human sarcopenia.
  1. Nat Commun. 2024 Sep 03. 15(1): 7677
    Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
    Elizabeth G Reisman, Javier Botella, Cheng Huang, Ralf B Schittenhelm, David A Stroud, Cesare Granata, Owala S Chandrasiri, Georg Ramm, Viola Oorschot, Nikeisha J Caruana, David J Bishop.
      Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.
    DOI:  https://doi.org/10.1038/s41467-024-50632-2
  2. Nat Metab. 2024 Sep 02.
    Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
    Ritsuko Nakai, Stella Varnum, Rachael L Field, Henyun Shi, Rocky Giwa, Wentong Jia, Samantha J Krysa, Eva F Cohen, Nicholas Borcherding, Russell P Saneto, Rick C Tsai, Masashi Suganuma, Hisashi Ohta, Takafumi Yokota, Jonathan R Brestoff.
      Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
    DOI:  https://doi.org/10.1038/s42255-024-01125-5
  3. Traffic. 2024 Sep;25(9): e12951
    Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.
    Huimei Liu, Hui Mao, Xueqian Ouyang, Ruirui Lu, Lanfang Li.
      Mitochondria, the dynamic organelles responsible for energy production and cellular metabolism, have the metabolic function of extracting energy from nutrients and synthesizing crucial metabolites. Nevertheless, recent research unveils that intercellular mitochondrial transfer by tunneling nanotubes, tumor microtubes, gap junction intercellular communication, extracellular vesicles, endocytosis and cell fusion may regulate mitochondrial function within recipient cells, potentially contributing to disease treatment, such as nonalcoholic steatohepatitis, glioblastoma, ischemic stroke, bladder cancer and neurodegenerative diseases. This review introduces the principal approaches to intercellular mitochondrial transfer and examines its role in various diseases. Furthermore, we provide a comprehensive overview of the inhibitors and activators of intercellular mitochondrial transfer, offering a unique perspective to illustrate the relationship between intercellular mitochondrial transfer and diseases.
    Keywords:  cell fusion; endocytosis; extracellular vesicles; gap junction intercellular communication; intercellular mitochondrial transfer; tumor microtube; tunneling nanotubes
    DOI:  https://doi.org/10.1111/tra.12951
  4. Mitochondrion. 2024 Aug 30. pii: S1567-7249(24)00108-9. [Epub ahead of print] 101950
    Mitochondrial transfer from mesenchymal stem cells: Mechanisms and functions.
    Qing Liu, Xiaoxin Zhang, Tongxin Zhu, Zhonghan Xu, Yingchun Dong, Bin Chen.
      Mesenchymal stem cells based therapy has been used in clinic for almost 20 years and has shown encouraging effects in treating a wide range of diseases. However, the underlying mechanism is far more complicated than it was previously assumed. Mitochondria transfer is one way that recently found to be employed by mesenchymal stem cells to exert its biological effects. As one way of exchanging mitochondrial components, mitochondria transfer determines both mesenchymal stem cells and recipient cell fates. In this review, we describe the factors that contribute to MSCs-MT. Then, the routes and mechanisms of MSCs-MT are summarized to provide a theoretical basis for MSCs therapy. Besides, the advantages and disadvantages of MSCs-MT in clinical application are analyzed.
    Keywords:  Biological effects; Extracellular vesicles; Mesenchymal stem cells; Mitochondrial transfer; Reactive oxygen species; Tunnelling nanotubes
    DOI:  https://doi.org/10.1016/j.mito.2024.101950
  5. Pharmacol Res. 2024 Aug 30. pii: S1043-6618(24)00327-X. [Epub ahead of print]208 107382
    Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.
    Veronica Marabitti, Elisabetta Vulpis, Francesca Nazio, Silvia Campello.
      It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy.
    Keywords:  Mitochondria transfer; cancer therapy; metabolic alterations; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2024.107382
  6. Skin Res Technol. 2024 Sep;30(9): e70022
    Effect of umbilical cord mesenchymal stem cell-derived mitochondrial transplantation on ischemia-reperfusion injury in a rat model.
    Chan Yeong Lee, Galina Khan, Dong Yun Hyun, Sang Hun Kim, Eun Soo Park.
       BACKGROUND: Despite advancements in reconstructive procedures, ischemia-reperfusion (I/R) injury remains a significant challenge in reconstructive surgery, with mitochondrial dysfunction playing a pivotal role. Mitochondrial transplantation has emerged as a promising therapeutic strategy to address this issue. This study aims to evaluate the impact of umbilical cord mesenchymal stem cell-derived mitochondrial transplantation on skin flap I/R models in rats.
    MATERIAL AND METHODS: Twenty male rats underwent I/R injury on skin flaps, with or without mitochondrial transplantation administered via intravenous or subcutaneous routes. Analysis encompassed histopathology, inflammatory, apoptotic, oxidative stress, and hypoxia markers.
    RESULTS: Results revealed a reduction in inflammation, apoptosis, oxidative stress, and hypoxia in the transplantation group compared to controls.
    CONCLUSION: The findings suggest that umbilical cord mesenchymal stem cell-derived mitochondrial transplantation shows promise in enhancing flap viability and attenuating I/R injury, offering valuable insights for improved outcomes in reconstructive surgery. However, further exploration in larger animal models and refinement of delivery methods and dosage are warranted to fully elucidate its clinical translatability.
    Keywords:  ischemia reperfusion injury; mitochondria; umbilical cord mesenchymal stem cells
    DOI:  https://doi.org/10.1111/srt.70022
  7. Clin Immunol. 2024 Aug 30. pii: S1521-6616(24)00459-5. [Epub ahead of print]267 110350
    The platelet-mitochondria nexus in autoimmune and musculoskeletal diseases.
    Despina Michailidou, Stavros Giaglis, George L Dale.
      Platelets are crucial for thrombosis and hemostasis. Importantly, they contain mitochondria that are responsible for energy generation and therefore vital for platelet survival and activation. Activated platelets can release mitochondria that may be free or encapsulated in platelet extracellular vesicles (EVs). Extruded mitochondria are a well-known source of mitochondrial DNA, and mitochondrial antigens that can be targeted by autoantibodies forming immune complexes (IC). Interaction of IC with the platelet cell surface FcγRIIA receptor results in platelet activation and release of platelet granule components. In this review, we summarize how platelets and mitochondria may contribute to the pathogenesis of different autoimmune and musculoskeletal diseases. Targeting key drivers of mitochondrial extrusion may ultimately lead to urgently needed targeted pharmacological interventions for treating inflammation and thrombotic diathesis, and halting organ damage in some of these rheumatological conditions.
    Keywords:  Autoimmune diseases; Mitochondria; Musculoskeletal diseases; Platelets
    DOI:  https://doi.org/10.1016/j.clim.2024.110350
  8. Nat Metab. 2024 Sep 02.
    Mitochondrial transplants to treat mitochondrial dysfunction.
    Alessandro Bitto.
      
    DOI:  https://doi.org/10.1038/s42255-024-01124-6
  9. J Histochem Cytochem. 2024 Sep 06. 221554241274882
    Frequent Icing Stimulates Skeletal Muscle Regeneration Following Injury With Necrosis in a Small Fraction of Myofibers in Rats.
    Masato Kawashima, Itsuki Nagata, Erika Terada, Asano Tamari, Mami Kurauchi, Tohma Sakuraya, Takahiro Sonomura, Eri Oyanagi, Hiromi Yano, Jonathan M Peake, Takamitsu Arakawa.
      Icing interventions on the injured skeletal muscle affect the macrophage-related regenerative events and muscle repair. However, despite its importance for the practice in sport medicine, the influence of different icing protocols on muscle regeneration remains unclear. Here, using a rodent model of mild muscle injury with necrosis in a small fraction of myofibers, the injured animals were allocated to four groups: non-icing control (Con) and a single treatment (Ice-1), three treatments (Ice-3), or nine treatments (Ice-9) with a 30-min icing each time within two days following injury. Muscle regeneration was compared between the groups on post-injury days 1, 3, 5, and 7. The results showed that compared with the Con group, muscle regeneration was faster in the Ice-9 group (but not in the Ice-1 and Ice-3 groups), as indicated by more rapid accumulation of satellite cells within the regenerating area and enlarged size of regenerating myofibers (p<0.05, respectively). There was also less macrophage accumulation (p<0.05) and a trend toward early removal of necrotic myofibers in the damaged/regenerating area in the Ice-9 group (p=0.0535). These results demonstrate that in the case of mild muscle damage, more frequent icing treatment is more effective to stimulate muscle regeneration.
    Keywords:  cryotherapy; inflammation; macrophages; muscle damage; regeneration
    DOI:  https://doi.org/10.1369/00221554241274882
  10. Biochem Biophys Res Commun. 2024 Aug 24. pii: S0006-291X(24)01142-2. [Epub ahead of print]733 150606
    Skeletal muscle atrophy induces memory dysfunction via hemopexin action in healthy young mice.
    Tsukasa Iki, Chihiro Tohda.
      Age-related morbidity has become an increasingly significant issue worldwide. Sarcopenia, the decline in skeletal muscle mass and strength with age, has been reported to be a risk factor for cognitive impairment. Our previous study revealed that skeletal muscle atrophy shifts the onset of memory dysfunction earlier in young Alzheimer's disease mice and found that hemopexin is a myokine responsible for memory loss. This study aimed to elucidate the occurrence of memory impairment due to skeletal muscle atrophy in non-genetically engineered healthy young mice and the involvement of hemopexin. Closed-colony ddY mice at 12-13 weeks of age were used. Both hind limbs were immobilized by cast attachment for 14 d. Casting for 2 weeks induced a loss of skeletal muscle weight. The memory function of the mice was evaluated using a novel object recognition test. The cast-attached mice exhibited memory impairment. Hemopexin levels in the conditioned medium of the skeletal muscle, plasma, and hippocampus were increased in cast-attached mice. Continuous intracerebroventricular hemopexin infusion induced memory deficits in non-cast mice. To investigate whether hemopexin is the main causative factor of cognitive impairment, cast-attached mice were intracerebroventricularly infused with an anti-hemopexin antibody. Cast-induced memory impairment was reversed by the infusion of an anti-hemopexin antibody. These findings provide new evidence that skeletal muscle atrophy causes memory impairment in healthy young mice through the action of hemopexin in the brain.
    Keywords:  Cast model; Cognitive impairment; Hemopexin; Muscle atrophy; Myokine
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150606
  11. FEBS Lett. 2024 Sep 03.
    Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
    Lishu Guo.
      The opening of the mitochondrial permeability transition pore (PTP), a Ca2+-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.
    Keywords:  F‐ATP synthase; cyclophilin D; ferroptosis; mitochondrial carrier homolog 2; mitochondrial permeability transition
    DOI:  https://doi.org/10.1002/1873-3468.15008
  12. J Cachexia Sarcopenia Muscle. 2024 Aug 29.
    Artificial neural network inference analysis identified novel genes and gene interactions associated with skeletal muscle aging.
    Janelle Tarum, Graham Ball, Thomas Gustafsson, Mikael Altun, Lívia Santos.
       BACKGROUND: Sarcopenia is an age-related muscle disease that increases the risk of falls, disabilities, and death. It is associated with increased muscle protein degradation driven by molecular signalling pathways including Akt and FOXO1. This study aims to identify genes, gene interactions, and molecular pathways and processes associated with muscle aging and exercise in older adults that remained undiscovered until now leveraging on an artificial intelligence approach called artificial neural network inference (ANNi).
    METHODS: Four datasets reporting the profile of muscle transcriptome obtained by RNA-seq of young (21-43 years) and older adults (63-79 years) were selected and retrieved from the Gene Expression Omnibus (GEO) data repository. Two datasets contained the transcriptome profiles associated to muscle aging and two the transcriptome linked to resistant exercise in older adults, the latter before and after 6 months of exercise training. Each dataset was individually analysed by ANNi based on a swarm neural network approach integrated into a deep learning model (Intelligent Omics). This allowed us to identify top 200 genes influencing (drivers) or being influenced (targets) by aging or exercise and the strongest interactions between such genes. Downstream gene ontology (GO) analysis of these 200 genes was performed using Metacore (Clarivate™) and the open-source software, Metascape. To confirm the differential expression of the genes showing the strongest interactions, real-time quantitative PCR (RT-qPCR) was employed on human muscle biopsies obtained from eight young (25 ± 4 years) and eight older men (78 ± 7.6 years), partaking in a 6-month resistance exercise training programme.
    RESULTS: CHAD, ZDBF2, USP54, and JAK2 were identified as the genes with the strongest interactions predicting aging, while SCFD1, KDM5D, EIF4A2, and NIPAL3 were the main interacting genes associated with long-term exercise in older adults. RT-qPCR confirmed significant upregulation of USP54 (P = 0.005), CHAD (P = 0.03), and ZDBF2 (P = 0.008) in the aging muscle, while exercise-related genes were not differentially expressed (EIF4A2 P = 0.99, NIPAL3 P = 0.94, SCFD1 P = 0.94, and KDM5D P = 0.64). GO analysis related to skeletal muscle aging suggests enrichment of pathways linked to bone development (adj P-value 0.006), immune response (adj P-value <0.001), and apoptosis (adj P-value 0.01). In older exercising adults, these were ECM remodelling (adj P-value <0.001), protein folding (adj P-value <0.001), and proteolysis (adj P-value <0.001).
    CONCLUSIONS: Using ANNi and RT-qPCR, we identified three strongly interacting genes predicting muscle aging, ZDBF2, USP54, and CHAD. These findings can help to inform the design of nonpharmacological and pharmacological interventions that prevent or mitigate sarcopenia.
    Keywords:  Aging; Artificial neural network; Exercise; Machine learning; Skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13562
  13. Am J Physiol Regul Integr Comp Physiol. 2024 Sep 06.
    Strenuous training combined with erythropoietin induces red cell volume expansion-mediated hypervolemia and alters systemic and skeletal muscle iron homeostasis.
    Benjamin J Ryan, David E Barney, Julie L McNiff, Devin J Drummer, Emily E Howard, Jess A Gwin, Christopher T Carrigan, Nancy E Murphy, Marques A Wilson, Stefan M Pasiakos, James P McClung, Lee M Margolis.
      Strenuous physical training increases total blood volume (BV) through expansion of plasma (PV) and red cell volumes (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, 8 healthy non-anemic males were treated with EPO (50 IU/kg body mass, 3x/week, subcutaneously) across 28 days of strenuous training (4d/week, exercise energy expenditures of 1334±24 kcal/d) while consuming a controlled, energy-balanced diet providing 39±4 mg/d iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased (p<0.01) RCV (13±6%) and BV (5±4%), whereas PV remained unchanged (p=0.86). The expansion of RCV was accompanied by a large decrease in whole-body iron stores, as indicated by decreased (p<0.01) ferritin (-77±10%) and hepcidin (-49±23%) concentrations in plasma. Training + EPO decreased (p<0.01) muscle protein abundance of ferritin (-25±20%) and increased (p<0.05) transferrin receptor (47±56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole-body and skeletal muscle iron stores.
    Keywords:  Blood Volume; Erythropoietin; Exercise Training; Iron Homeostasis
    DOI:  https://doi.org/10.1152/ajpregu.00164.2024
  14. ACS Appl Mater Interfaces. 2024 Aug 29.
    Human Skeletal Muscle Myoblast Culture in Aligned Bacterial Nanocellulose and Commercial Matrices.
    Melina Mastrodimos, Saumya Jain, Maryam Badv, Jun Shen, Hossein Montazerian, Claire E Meyer, Nasim Annabi, Paul S Weiss.
      Bacterial nanocellulose (BNC) is a durable, flexible, and dynamic biomaterial capable of serving a wide variety of fields, sectors, and applications within biotechnology, healthcare, electronics, agriculture, fashion, and others. BNC is produced spontaneously in carbohydrate-rich bacterial culture media, forming a cellulosic pellicle via a nanonetwork of fibrils extruded from certain genera. Herein, we demonstrate engineering BNC-based scaffolds with tunable physical and mechanical properties through postprocessing. Human skeletal muscle myoblasts (HSMMs) were cultured on these scaffolds, and in vitro electrical stimulation was applied to promote cellular function for tissue engineering applications. We compared physiologic maturation markers of human skeletal muscle myoblast development using a 2.5-dimensional culture paradigm in fabricated BNC scaffolds, compared to two-dimensional (2D) controls. We demonstrate that the culture of human skeletal muscle myoblasts on BNC scaffolds developed under electrical stimulation produced highly aligned, physiologic morphology of human skeletal muscle myofibers compared to unstimulated BNC and standard 2D culture. Furthermore, we compared an array of metrics to assess the BNC scaffold in a rigorous head-to-head study with commercially available, clinically approved matrices, Kerecis Omega3 Wound Matrix (Marigen) and Phoenix as well as a gelatin methacryloyl (GelMA) hydrogel. The BNC scaffold outcompeted industry standard matrices as well as a 20% GelMA hydrogel in durability and sustained the support of human skeletal muscle myoblasts in vitro. This work offers a robust demonstration of BNC scaffold cytocompatibility with human skeletal muscle cells and sets the basis for future work in healthcare, bioengineering, and medical implant technological development.
    Keywords:  aligned; bacterial nanocellulose; bioreactor; electrically stimulated; epitaxial; human skeletal muscle myoblasts; hydrogel; mesh; soft-tissue reconstruction
    DOI:  https://doi.org/10.1021/acsami.4c07612
  15. J Cachexia Sarcopenia Muscle. 2024 Sep 05.
    Neuromuscular impairment at different stages of human sarcopenia.
    Fabio Sarto, Martino V Franchi, Jamie S McPhee, Daniel W Stashuk, Matteo Paganini, Elena Monti, Maira Rossi, Giuseppe Sirago, Sandra Zampieri, Evgeniia S Motanova, Giacomo Valli, Tatiana Moro, Antonio Paoli, Roberto Bottinelli, Maria A Pellegrino, Giuseppe De Vito, Helen M Blau, Marco V Narici.
       BACKGROUND: Degeneration of the motoneuron and neuromuscular junction (NMJ) and loss of motor units (MUs) contribute to age-related muscle wasting and weakness associated with sarcopenia. However, these features have not been comprehensively investigated in humans. This study aimed to compare neuromuscular system integrity and function at different stages of sarcopenia, with a particular focus on NMJ stability and MU properties.
    METHODS: We recruited 42 young individuals (Y) (aged 25.98 ± 4.6 years; 57% females) and 88 older individuals (aged 75.9 ± 4.7 years; 55% females). The older group underwent a sarcopenia screening according to the revised guidelines of the European Working Group on Sarcopenia in Older People 2. In all groups, knee extensor muscle force was evaluated by isometric dynamometry, muscle morphology by ultrasound and MU potential properties by intramuscular electromyography (iEMG). MU number estimate (iMUNE) and blood samples were obtained. Muscle biopsies were collected in a subgroup of 16 Y and 52 older participants.
    RESULTS: Thirty-nine older individuals were non-sarcopenic (NS), 31 pre-sarcopenic (PS) and 18 sarcopenic (S). A gradual decrease in quadriceps force, cross-sectional area and appendicular lean mass was observed across the different stages of sarcopenia (for all P < 0.0001). Handgrip force and the Short Physical Performance Battery score also showed a diminishing trend. iEMG analyses revealed elevated near fibre segment jitter in NS, PS and S compared with Y (Y vs. NS and S: P < 0.0001; Y vs. PS: P = 0.0169), suggestive of age-related impaired NMJ transmission. Increased C-terminal agrin fragment (P < 0.0001) and altered caveolin 3 protein expression were consistent with age-related NMJ instability in all the older groups. The iMUNE was lower in all older groups (P < 0.0001), confirming age-related loss of MUs. An age-related increase in MU potential complexity was also observed. These observations were accompanied by increased muscle denervation and axonal damage, evinced by the increase in neural cell adhesion molecule-positive fibres (Y vs. NS: P < 0.0001; Y vs. S: P = 0.02) and the increase in serum concentration of neurofilament light chain (P < 0.0001), respectively. Notably, most of these MU and NMJ parameters did not differ when comparing older individuals with or without sarcopenia.
    CONCLUSIONS: Alterations in MU properties, axonal damage, an altered innervation profile and NMJ instability are prominent features of the ageing of the neuromuscular system. These neuromuscular alterations are accompanied by muscle wasting and weakness; however, they appear to precede clinically diagnosed sarcopenia, as they are already detectable in older NS individuals.
    Keywords:  electromyography; fibre denervation; motoneuron; motor units; muscle atrophy; neuromuscular junction
    DOI:  https://doi.org/10.1002/jcsm.13531
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