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Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging
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Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 5074

Special Issue Editor

Dr. Rosa Mancinelli

E-Mail Website
Guest Editor
Department of Neuroscience, Imaging and Clinical Sciences, University “G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
Interests: muscle; skeletal
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is known that in humans, skeletal muscles account for about 40% of the body weight and are essential for overall health. With increasing age, muscle function declines, causing reduced mobility, thus leading to reduced independence and an increase in morbidity and mortality in the elderly. This age-related decline in muscle function is known as sarcopenia. Sarcopenia is a multifactorial disease that is defined as a progressive loss of muscle mass, strength, and function. It has attracted great research efforts to clarify its underlying mechanisms and potential treatments.

When aiming to discover hallmarks of aging, looking at shared age- and disease-related changes in cellular and muscular pathways such as apoptosis, cell cycle regulation, calcium handling, myokines, and catabolism can be helpful.

The aim of this Special Issue is essentially to collect new discoveries and study approaches to aging processes, mainly at the molecular and neuromuscular levels. For this Special Issue, we invite researchers to provide original research articles and review articles regarding results in the field of the new frontiers that can contribute to the understanding of the aging muscle process.

Dr. Rosa Mancinelli
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • aging
  • sarcopenia
  • neuromuscular junction
  • molecular muscle modifications
  • myokines

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Published Papers (6 papers)

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Research

12 pages, 2839 KiB  
Article
Acute and Chronic Resistance Training, Acute Endurance Exercise, nor Physiologically Plausible Lactate In Vitro Affect Skeletal Muscle Lactylation
by Madison L. Mattingly, Derick A. Anglin, Bradley A. Ruple, Maira C. Scarpelli, Joao G. Bergamasco, Joshua S. Godwin, Christopher B. Mobley, Andrew D. Frugé, Cleiton A. Libardi and Michael D. Roberts
Int. J. Mol. Sci. 2024, 25(22), 12216; https://doi.org/10.3390/ijms252212216 - 14 Nov 2024
Viewed by 445
Abstract
We examined changes in skeletal muscle protein lactylation and acetylation in response to acute resistance exercise, chronic resistance training (RT), and a single endurance cycling bout. Additionally, we performed in vitro experiments to determine if different sodium lactate treatments affect myotube protein lactylation [...] Read more.
We examined changes in skeletal muscle protein lactylation and acetylation in response to acute resistance exercise, chronic resistance training (RT), and a single endurance cycling bout. Additionally, we performed in vitro experiments to determine if different sodium lactate treatments affect myotube protein lactylation and acetylation. The acute and chronic RT study (12 college-aged participants) consisted of 10 weeks of unilateral leg extensor RT with vastus lateralis (VL) biopsies taken at baseline, 24 h following the first RT bout, and the morning of the last day of the RT bout. For the acute cycling study (9 college-aged participants), VL biopsies were obtained before, 2 h after, and 8 h after 60 min of cycling. For in vitro experiments, C2C12 myotubes were treated with varying levels of sodium lactate, including LOW (1 mM for 24 h), HIGH (10 mM for 24 h), and PULSE (10 mM for 30 min followed by 1 mM for 23.5-h). Neither acute nor chronic RT significantly affected nuclear or cytoplasmic protein lactylation. However, cytoplasmic protein acetylation was significantly reduced following one RT bout (−15%, p = 0.002) and chronic RT (−16%, p = 0.006). Cycling did not acutely alter post-exercise global protein lactylation or acetylation patterns. Lastly, varying 24 h lactate treatments did not alter nuclear or cytoplasmic protein lactylation or acetylation, cytoplasmic protein synthesis levels, or myotube diameters. These findings continue to support the idea that exercise induces more dynamic changes in skeletal muscle protein acetylation, but not lactylation. However, further human research with more sampling timepoints and a lactylomics approach are needed to determine if, at all, different exercise modalities affect skeletal muscle protein lactylation. Full article
(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)
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17 pages, 4728 KiB  
Article
Nrf2 Deficiency Exacerbates the Decline in Swallowing and Respiratory Muscle Mass and Function in Mice with Aspiration Pneumonia
by Hikaru Hashimoto, Tatsuma Okazaki, Yohei Honkura, Yuzhuo Ren, Peerada Ngamsnae, Takuma Hisaoka, Yasutoshi Koshiba, Jun Suzuki, Satoru Ebihara and Yukio Katori
Int. J. Mol. Sci. 2024, 25(21), 11829; https://doi.org/10.3390/ijms252111829 - 4 Nov 2024
Viewed by 570
Abstract
Aspiration pneumonia exacerbates swallowing and respiratory muscle atrophy. It induces respiratory muscle atrophy through three steps: proinflammatory cytokine production, caspase-3 and calpain, and then ubiquitin–proteasome activations. In addition, autophagy induces swallowing muscle atrophy. Nrf2 is the central detoxifying and antioxidant gene whose function [...] Read more.
Aspiration pneumonia exacerbates swallowing and respiratory muscle atrophy. It induces respiratory muscle atrophy through three steps: proinflammatory cytokine production, caspase-3 and calpain, and then ubiquitin–proteasome activations. In addition, autophagy induces swallowing muscle atrophy. Nrf2 is the central detoxifying and antioxidant gene whose function in aspiration pneumonia is unclear. We explored the role of Nrf2 in aspiration pneumonia by examining swallowing and respiratory muscle mass and function using wild-type and Nrf2-knockout mice. Pepsin and lipopolysaccharide aspiration challenges caused aspiration pneumonia. The swallowing (digastric muscles) and respiratory (diaphragm) muscles were isolated. Quantitative RT-PCR and Western blotting were used to assess their proteolysis cascade. Pathological and videofluoroscopic examinations evaluated atrophy and swallowing function, respectively. Nrf2-knockouts showed exacerbated aspiration pneumonia compared with wild-types. Nrf2-knockouts exhibited more persistent and intense proinflammatory cytokine elevation than wild-types. In both mice, the challenge activated calpains and caspase-3 in the diaphragm but not in the digastric muscles. The digastric muscles showed extended autophagy activation in Nrf2-knockouts compared to wild-types. The diaphragms exhibited autophagy activation only in Nrf2-knockouts. Nrf2-knockouts showed worsened muscle atrophies and swallowing function compared with wild-types. Thus, activation of Nrf2 may alleviate inflammation, muscle atrophy, and function in aspiration pneumonia, a major health problem for the aging population, and may become a therapeutic target. Full article
(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)
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15 pages, 9325 KiB  
Article
Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy
by Sören Janßen, Leoni S. Erbe, Moritz Kneifel, Matthias Vorgerd, Kristina Döring, Krzysztof P. Lubieniecki, Joanna M. Lubieniecka, Wanda M. Gerding, Nicolas Casadei, Anne-Katrin Güttsches, Christoph Heyer, Thomas Lücke, Hoa Huu Phuc Nguyen, Cornelia Köhler and Sabine Hoffjan
Int. J. Mol. Sci. 2024, 25(19), 10867; https://doi.org/10.3390/ijms251910867 - 9 Oct 2024
Viewed by 889
Abstract
Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe [...] Read more.
Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype–phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient’s phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype–phenotype correlations. Full article
(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)
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13 pages, 19310 KiB  
Article
Cross-Species Studies Reveal That Dysregulated Mitochondrial Gene Expression and Electron Transport Complex I Activity Are Crucial for Sarcopenia
by Ji-Yoon Lee, Su-Kyung Shin, Ji-Won Han, Eun-Young Kwon and Heekyong R. Bae
Int. J. Mol. Sci. 2024, 25(19), 10302; https://doi.org/10.3390/ijms251910302 - 25 Sep 2024
Viewed by 696
Abstract
The significance of complex I of the electron transport chain (ETC) in the aging process is widely acknowledged; however, its specific impact on the development of sarcopenia in muscle remains poorly understood. This study elucidated the correlation between complex I inhibition and sarcopenia [...] Read more.
The significance of complex I of the electron transport chain (ETC) in the aging process is widely acknowledged; however, its specific impact on the development of sarcopenia in muscle remains poorly understood. This study elucidated the correlation between complex I inhibition and sarcopenia by conducting a comparative analysis of skeletal muscle gene expression in sarcopenia phenotypes from rats, mice, and humans. Our findings reveal a common mechanistic link across species, particularly highlighting the correlation between the suppression of complex I of ETC activity and dysregulated mitochondrial transcription and translation in sarcopenia phenotypes. Additionally, we observed macrophage dysfunction alongside abnormal metabolic processes within skeletal muscle tissues across all species, implicating their pathogenic role in the onset of sarcopenia. These discoveries underscore the importance of understanding the shared mechanisms associated with complex I of ETC in sarcopenia development. The identified correlations provide valuable insights into potential targets for therapeutic interventions aimed at mitigating the impact of sarcopenia, a condition with substantial implications for aging populations. Full article
(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)
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19 pages, 21062 KiB  
Article
Functional and Structural Changes in Diaphragm Neuromuscular Junctions in Early Aging
by Andrei N. Tsentsevitsky, Guzel V. Sibgatullina, Yulia G. Odoshivkina, Venera F. Khuzakhmetova, Anna R. Tokmakova, Anastasia A. Ponomareva, Vadim V. Salnikov, Guzalia F. Zakirjanova, Alexey M. Petrov and Ellya A. Bukharaeva
Int. J. Mol. Sci. 2024, 25(16), 8959; https://doi.org/10.3390/ijms25168959 - 17 Aug 2024
Viewed by 1009
Abstract
Age-related impairment of the diaphragm causes respiratory complications. Neuromuscular junction (NMJ) dysfunction can be one of the triggering events in diaphragm weaknesses in old age. Prominent structural and functional alterations in diaphragm NMJs were described in elderly rodents, but NMJ changes in middle [...] Read more.
Age-related impairment of the diaphragm causes respiratory complications. Neuromuscular junction (NMJ) dysfunction can be one of the triggering events in diaphragm weaknesses in old age. Prominent structural and functional alterations in diaphragm NMJs were described in elderly rodents, but NMJ changes in middle age remain unclear. Here, we compared diaphragm muscles from young adult (3 months) and middle-aged (12 months) BALB/c mice. Microelectrode recordings, immunofluorescent staining, electron microscopy, myography, and whole-body plethysmography were used. We revealed presynaptic (i) and postsynaptic (ii) changes. The former (i) included an increase in both action potential propagation velocity and neurotransmitter release evoked by low-, moderate-, and high-frequency activity but a decrease in immunoexpression of synapsin 1 and synaptic vesicle clustering. The latter (ii) consisted of a decrease in currents via nicotinic acetylcholine receptors and the area of their distribution. These NMJ changes correlated with increased contractile responses to moderate- to high-frequency nerve activation. Additionally, we found alterations in the pattern of respiration (an increase in peak inspiratory flow and a tendency of elevation of the tidal volume), which imply increased diaphragm activity in middle-aged mice. We conclude that enhancement of neuromuscular communication (due to presynaptic mechanism) accompanied by improved contractile responses occurs in the diaphragm in early aging. Full article
(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)
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27 pages, 3498 KiB  
Article
Molecular Adaptations of BDNF/NT-4 Neurotrophic and Muscarinic Pathways in Ageing Neuromuscular Synapses
by Marta Balanyà-Segura, Aleksandra Polishchuk, Laia Just-Borràs, Víctor Cilleros-Mañé, Carolina Silvera, Anna Ardévol, Marta Tomàs, Maria A. Lanuza, Erica Hurtado and Josep Tomàs
Int. J. Mol. Sci. 2024, 25(15), 8018; https://doi.org/10.3390/ijms25158018 - 23 Jul 2024
Viewed by 824
Abstract
Age-related conditions, such as sarcopenia, cause physical disabilities for an increasing section of society. At the neuromuscular junction, the postsynaptic-derived neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) have neuroprotective functions and contribute to the correct regulation of the exocytotic machinery. [...] Read more.
Age-related conditions, such as sarcopenia, cause physical disabilities for an increasing section of society. At the neuromuscular junction, the postsynaptic-derived neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) have neuroprotective functions and contribute to the correct regulation of the exocytotic machinery. Similarly, presynaptic muscarinic signalling plays a fundamental modulatory function in this synapse. However, whether or not these signalling pathways are compromised in ageing neuromuscular system has not yet been analysed. The present study analyses, through Western blotting, the differences in expression and activation of the main key proteins of the BDNF/NT-4 and muscarinic pathways related to neurotransmission in young versus ageing Extensor digitorum longus (EDL) rat muscles. The main results show an imbalance in several sections of these pathways: (i) a change in the stoichiometry of BDNF/NT-4, (ii) an imbalance of Tropomyosin-related kinase B receptor (TrkB)-FL/TrkB-T1 and neurotrophic receptor p 75 (p75NTR), (iii) no changes in the cytosol/membrane distribution of phosphorylated downstream protein kinase C (PKC)βI and PKCε, (iv) a reduction in the M2-subtype muscarinic receptor and P/Q-subtype voltage-gated calcium channel, (v) an imbalance of phosphorylated mammalian uncoordinated-18-1 (Munc18-1) (S313) and synaptosomal-associated protein 25 (SNAP-25) (S187), and (vi) normal levels of molecules related to the management of acetylcholine (Ach). Based on this descriptive analysis, we hypothesise that these pathways can be adjusted to ensure neurotransmission rather than undergoing negative alterations caused by ageing. However, further studies are needed to assess this hypothetical suggestion. Our results contribute to the understanding of some previously described neuromuscular functional age-related impairments. Strategies to promote these signalling pathways could improve the neuromuscular physiology and quality of life of older people. Full article
(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)
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