bims-musmir 2024-11-03 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–11–03
fourteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Alternatively spliced MAP4 isoforms have key roles in maintaining microtubule organization and skeletal muscle function.
Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations.
Sex dimorphism and tissue specificity of gene expression changes in aging mice.
Transcriptional Analysis of Cancer Cachexia: Conserved and Unique Features Across Pre-Clinical Models and Biological Sex.
Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.
Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.
The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.
Compound heterozygous RYR1-RM mouse model reveals disease pathomechanisms and muscle adaptations to promote postnatal survival.
A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).
Surviving septic patients endotyped with a functional assay demonstrate active immune responses.
Profiling the transcriptomic age of single-cells in humans.
Ageing leads to selective type II myofibre deterioration and denervation independent of reinnervative capacity in human skeletal muscle.
Neuromuscular mechanisms for the fast decline in rate of force development with muscle disuse - a narrative review.
Chemokine CCL2 and its receptor CCR2 in different age groups of patients with COVID-19.

iScience. 2024 Nov 15. 27(11): 111104

Alternatively spliced MAP4 isoforms have key roles in maintaining microtubule organization and skeletal muscle function.

Lathan Lucas, Larissa Nitschke, Brandon Nguyen, James A Loehr, George G Rodney, Thomas A Cooper.

  Skeletal muscle cells (myofibers) are elongated non-mitotic, multinucleated syncytia that have adapted a microtubule lattice. Microtubule-associated proteins (MAPs) play roles in regulating microtubule architecture. The most abundant MAP in skeletal muscle is MAP4. MAP4 consists of a ubiquitous MAP4 isoform (uMAP4), expressed in most tissues, and a striated-muscle-specific alternatively spliced isoform (mMAP4) that includes a 3,180-nucleotide exon (exon 8). To determine the role of mMAP4 in skeletal muscle, we generated mice that lack mMAP4 and express only uMAP4 due to genomic deletion of exon 8. We demonstrate that loss of mMAP4 leads to disorganized microtubule architecture and intrinsic loss of force generation. We show that mMAP4 exhibits enhanced association with microtubules compared to uMAP4 and that both the loss of mMAP4 and the concomitant gain of uMAP4 cause loss of muscle function. These results demonstrate the critical role for balanced expression of mMAP4 and uMAP4 for skeletal muscle homeostasis.

Keywords:  Cellular physiology; Functional aspects of cell biology; Molecular Structure; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2024.111104
Nat Commun. 2024 Oct 30. 15(1): 9372

Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations.

Chengyi Sun, Casey O Swoboda, Fabian Montecino Morales, Cristofer Calvo, Michael J Petrany, Sreeja Parameswaran, Andrew VonHandorf, Matthew T Weirauch, Christoph Lepper, Douglas P Millay.

Multinucleated skeletal muscle cells need to acquire additional nuclei through fusion with activated skeletal muscle stem cells when responding to both developmental and adaptive growth stimuli. A fundamental question in skeletal muscle biology has been the reason underlying this need for new nuclei in cells that already harbor hundreds of nuclei. Here we utilize nuclear RNA-sequencing approaches and develop a lineage tracing strategy capable of defining the transcriptional state of recently fused nuclei and distinguishing this state from that of pre-existing nuclei. Our findings reveal the presence of conserved markers of newly fused nuclei both during development and after a hypertrophic stimulus in the adult. However, newly fused nuclei also exhibit divergent gene expression that is determined by the myogenic environment to which they fuse. Moreover, accrual of new nuclei through fusion is required for nuclei already resident in adult myofibers to mount a normal transcriptional response to a load-inducing stimulus. We propose a model of mutual regulation in the control of skeletal muscle development and adaptations, where newly fused and pre-existing myonuclear populations influence each other to maintain optimal functional growth.

DOI: https://doi.org/10.1038/s41467-024-53510-z
Biol Sex Differ. 2024 Oct 31. 15(1): 89

Sex dimorphism and tissue specificity of gene expression changes in aging mice.

Dantong Zhu, Matt Arnold, Brady A Samuelson, Judy Z Wu, Amber Mueller, David A Sinclair, Alice E Kane.

   BACKGROUND: Aging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues.
METHODS: We collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type.
RESULTS: We identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction.
CONCLUSIONS: There are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging.

Keywords:  Adipose tissue; Aging; Co-expression network analysis; Feature selection; Gene expression; Liver; Mice; Muscle; Sex dimorphism; Tissue-specific

DOI:  https://doi.org/10.1186/s13293-024-00666-4
Am J Physiol Cell Physiol. 2024 Oct 28.

Transcriptional Analysis of Cancer Cachexia: Conserved and Unique Features Across Pre-Clinical Models and Biological Sex.

Francielly Morena, Ana Regina Cabrera, Ronald G Jones Iii, Eleanor R Schrems, Ruqaiza Muhyudin, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.

  Studies suggest heterogeneity in cancer cachexia (CC) among models and biological sexes, yet examinations comparing models and sexes are scarce. We compared the transcriptional landscape of skeletal muscle across murine CC models and biological sexes during early and late CC. Global gene expression analyses were performed on gastrocnemius (LLC-Lewis Lung Carcinoma), quadriceps (KPC-pancreatic), and tibialis anterior (C26-colorectal and ApcMin/+) muscles across biological sexes. Differentially expressed genes (DEGs) were identified using an adj-p-value of <0.05, followed by pathway and computational cistrome analyses. Integrating all controls, early, and late-stage of all models and sexes revealed up to 68% of DEGs and pathways were enriched at early and late CC, indicating a conserved transcriptional profile during CC development. Comparing DEGs and pathways within sexes and across models, in early-CC, the transcriptional response was highly heterogeneous. At late-stage, 11.5% of upregulated and 10% of downregulated genes were shared between models in males, while 18.9% of upregulated and 7% of downregulated DEGs were shared in females. Shared DEGs were enriched in proteasome and mitophagy/autophagy pathways (upregulated), and downregulation of energy metabolism pathways in males only. Between sexes, though proportion of shared DEGs was low (<16%), similar pathway enrichment was observed, including proteasome and mitophagy at late-stage CC. In early-CC, Osmr upregulation was the only commonality across all models and sexes, while CLOCK and ARNTL/BMAL1 were predicted transcriptional factors associated with dysregulations in all three male models. This study highlights sex and model differences in CC progression and suggests conserved transcriptional changes as potential therapeutic targets.

Keywords:  RNA-sequencing; colon cancer; heterogeneity; lung cancer; pancreatic cancer

DOI:  https://doi.org/10.1152/ajpcell.00647.2024
bioRxiv. 2024 Oct 25. pii: 2024.10.22.619751. [Epub ahead of print]

Mitochondrial-targeted plastoquinone therapy ameliorates early onset muscle weakness that precedes ovarian cancer cachexia in mice.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Luke D Flewwelling, Nathaniel J Andrews, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Stavroula Tsitkanou, Jeremy A Simpson, Nicholas P Greene, Arthur J Cheng, Jim Petrik, Christopher G R Perry.

Cancer cachexia, and the related loss of muscle and strength, worsens quality of life and lowers overall survival. Recently, a novel 'pre-atrophy' muscle weakness was identified during early-stage cancer. While mitochondrial stress responses are associated with early-stage pre-atrophy weakness, a causal relationship has not been established. Using a robust mouse model of metastatic epithelial ovarian cancer (EOC)-induced cachexia, we found the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents pre-atrophy weakness in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. EOC reduced flexor digitorum brevis (FDB) force production and myoplasmic free calcium ([Ca 2+ ] i ) during contraction in single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout EOC. These discoveries identify that muscle weakness can occur independent of atrophy throughout EOC in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force during the early pre-atrophy period and in late-stage EOC once cachexia has become severe.

DOI: https://doi.org/10.1101/2024.10.22.619751
Nat Commun. 2024 Oct 25. 15(1): 9218

Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.

Pihu Mehrotra, James Jablonski, John Toftegaard, Yali Zhang, Shahryar Shahini, Jianmin Wang, Carey W Hung, Reilly Ellis, Gabriella Kayal, Nika Rajabian, Song Liu, Kelly C S Roballo, Susan B Udin, Stelios T Andreadis, Kirkwood E Personius.

Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. PNI is characterized by nerve degeneration distal to the site of nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of "accepting" innervation because of the slow speed of axon regeneration post injury. We hypothesize that reprogramming the skeletal muscle to an embryonic-like state may preserve its reinnervation capability following PNI. To this end, we generate a mouse model in which NANOG, a pluripotency-associated transcription factor is expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulates the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression leads to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation. Further, NANOG mice demonstrate extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice show greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses and isometric force production. In conclusion, we demonstrate that reprogramming muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.

DOI: https://doi.org/10.1038/s41467-024-53276-4
EMBO Rep. 2024 Oct 31.

The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.

Sebastian Edman, Ronald G Jones Iii, Paulo R Jannig, Rodrigo Fernandez-Gonzalo, Jessica Norrbom, Nicholas T Thomas, Sabin Khadgi, Pieter J Koopmans, Francielly Morena, Toby L Chambers, Calvin S Peterson, Logan N Scott, Nicholas P Greene, Vandre C Figueiredo, Christopher S Fry, Liu Zhengye, Johanna T Lanner, Yuan Wen, Björn Alkner, Kevin A Murach, Ferdinand von Walden.

  A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery. To test whether MYC is sufficient for hypertrophy, we periodically pulse MYC in skeletal muscle over 4 weeks. Transient MYC increases muscle mass and fiber size in the soleus of adult mice. We present a temporally resolved resource for understanding molecular adaptations to resistance exercise in muscle ( http://data.myoanalytics.com ) and suggest that controlled MYC doses influence the exercise-related hypertrophic transcriptional landscape.

Keywords:  Biopsy; Methylome; Time Course; Transcription Factors; Transcriptome

DOI:  https://doi.org/10.1038/s44319-024-00299-z
FASEB J. 2024 Oct;38(20): e70120

Compound heterozygous RYR1-RM mouse model reveals disease pathomechanisms and muscle adaptations to promote postnatal survival.

Chen Liang, Sundeep Malik, Miao He, Linda Groom, Sara K Ture, Thomas N O'Connor, Craig N Morrell, Robert T Dirksen.

  Pathogenic variants in the type I ryanodine receptor (RYR1) result in a wide range of muscle disorders referred to as RYR1-related myopathies (RYR1-RM). We developed the first RYR1-RM mouse model resulting from co-inheritance of two different RYR1 missense alleles (Ryr1TM/SC-ΔL mice). Ryr1TM/SC-ΔL mice exhibit a severe, early onset myopathy characterized by decreased body/muscle mass, muscle weakness, hypotrophy, reduced RYR1 expression, and unexpectedly, incomplete postnatal lethality with a plateau survival of ~50% at 12 weeks of age. Ryr1TM/SC-ΔL mice display reduced respiratory function, locomotor activity, and in vivo muscle strength. Extensor digitorum longus muscles from Ryr1TM/SC-ΔL mice exhibit decreased cross-sectional area of type IIb and type IIx fibers, as well as a reduction in number of type IIb fibers. Ex vivo functional analyses revealed reduced Ca2+ release and specific force production during electrically-evoked twitch stimulation. In spite of a ~threefold reduction in RYR1 expression in single muscle fibers from Ryr1TM/SC-ΔL mice at 4 weeks and 12 weeks of age, RYR1 Ca2+ leak was not different from that of fibers from control mice at either age. Proteomic analyses revealed alterations in protein synthesis, folding, and degradation pathways in the muscle of 4- and 12-week-old Ryr1TM/SC-ΔL mice, while proteins involved in the extracellular matrix, dystrophin-associated glycoprotein complex, and fatty acid metabolism were upregulated in Ryr1TM/SC-ΔL mice that survive to 12 weeks of age. These findings suggest that adaptations that optimize RYR1 expression/Ca2+ leak balance, sarcolemmal stability, and fatty acid biosynthesis provide Ryr1TM/SC-ΔL mice with an increased survival advantage during postnatal development.

Keywords:  calcium signaling; congenital myopathy; excitation‐contraction coupling; proteomics; ryanodine receptor; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202401189R
Biomolecules. 2024 Oct 03. pii: 1252. [Epub ahead of print]14(10):

A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).

Stephen Henry Holland, Ricardo Carmona-Martinez, Kaela O'Connor, Daniel O'Neil, Andreas Roos, Sally Spendiff, Hanns Lochmüller.

  The neuromuscular junction (NMJ) is the site where the motor neuron innervates skeletal muscle, enabling muscular contraction. Congenital myasthenic syndromes (CMS) arise when mutations in any of the approximately 35 known causative genes cause impaired neuromuscular transmission at the NMJ, resulting in fatigable muscle weakness. A subset of five of these CMS-causative genes are associated with protein glycosylation. Glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) is the rate-limiting enzyme within the hexosamine biosynthetic pathway (HBP), a metabolic pathway that produces the precursors for glycosylation. We hypothesized that deficiency in Gfpt1 expression results in aberrant or reduced glycosylation, impairing the proper assembly and stability of key NMJ-associated proteins. Using both in vitro and in vivo Gfpt1-deficient models, we determined that the acetylcholine receptor delta subunit (AChRδ) has reduced expression and is hypo-glycosylated. Using laser capture microdissection, NMJs were harvested from Gfpt1 knockout mouse muscle. A lower-molecular-weight species of AChRδ was identified at the NMJ that was not detected in controls. Furthermore, Gfpt1-deficient muscle lysates showed impairment in protein O-GlcNAcylation and sialylation, suggesting that multiple glycan chains are impacted. Other key NMJ-associated proteins, in addition to AChRδ, may also be differentially glycosylated in Gfpt1-deficient muscle.

Keywords:  O-GlcNAcylation; acetylcholine receptor delta subunit (AChRδ); congenital myasthenic syndrome (CMS); glutamine-fructose-6-phosphate transaminase 1 (Gfpt1); glycosylation; neuromuscular junction (NMJ)

DOI:  https://doi.org/10.3390/biom14101252
Front Immunol. 2024 ;15 1418613

Surviving septic patients endotyped with a functional assay demonstrate active immune responses.

Adam D Price, Ellen R Becker, Evan L Barrios, Monty B Mazer, Patrick W McGonagill, Christian B Bergmann, Michael D Goodman, Robert W Gould, Mahil Rao, Valerie E Polcz, Tamara A Kucaba, Andrew H Walton, Sydney Miles, Julie Xu, Muxuan Liang, Tyler J Loftus, Philip A Efron, Kenneth E Remy, Scott C Brakenridge, Vladimir P Badovinac, Thomas S Griffith, Lyle L Moldawer, Richard S Hotchkiss, Charles C Caldwell.

   Introduction: Sepsis is a complex clinical syndrome characterized by a heterogenous host immune response. Historically, static protein and transcriptomic metrics have been employed to describe the underlying biology. Here, we tested the hypothesis that ex vivo functional TNF expression as well as an immunologic endotype based on both IFNγ and TNF expression could be used to model clinical outcomes in sepsis patients.
Methods: This prospective, observational study of patient samples collected from the SPIES consortium included patients at five health systems enrolled over 17 months, with 46 healthy control patients, 68 ICU patients without sepsis, and 107 ICU patients with sepsis. Whole blood was collected on day 1, 4, and 7 of ICU admission. Outcomes included in-hospital and 180-day mortality and non-favorable discharge disposition defined by skilled nursing facility, long-term acute care facility, or hospice. Whole blood ELISpot assays were conducted to quantify TNF expression [stimulated by lipopolysaccharide (LPS)] and IFNγ expression (stimulated by anti-CD3/CD28 mAb), which were then used for assignment to one of four subgroups including an 'immunocompetent', 'immunosuppressed endotype', and two 'mixed' endotypes.
Results: Whole blood TNF spot-forming units were significantly increased in septic and CINS patients on days 4 and 7 compared to healthy subjects. In contrast, TNF expression per cell on days 1, 4, and 7 was significantly lower in both septic and critically ill non-septic (CINS) patients compared to healthy subjects. Early increases in total TNF expression were associated with favorable discharge disposition and lower in-hospital mortality. 'Immunocompetent' endotype patients on day 1 had a higher proportion of favorable to non-favorable discharges compared to the 'immunosuppressed' endotype. Similarly, 'immunocompetent' endotype patients on day 4 had a higher in-hospital survival compared to the 'immunosuppressed' endotype patients. Finally, among septic patients, decreased total TNF and IFNγ expression were associated with 180-day mortality.
Conclusions: Increased ex vivo whole blood TNF expression is associated with improved clinical outcomes. Further, the early 'immunocompetent' endotype is associated with favorable discharge and improved in-hospital and 180-day survival. The ability to functionally stratify septic patients based on blood cell function ex vivo may allow for identification of future immune modulating therapies.

Keywords:  IL-6; critical illness; late mortality; prediction modeling; procalcitonin

DOI:  https://doi.org/10.3389/fimmu.2024.1418613
Commun Biol. 2024 Oct 26. 7(1): 1397

Profiling the transcriptomic age of single-cells in humans.

Enikő Zakar-Polyák, Attila Csordas, Róbert Pálovics, Csaba Kerepesi.

Although aging clocks predicting the age of individual organisms have been extensively studied, the age of individual cells remained largely unexplored. Most recently single-cell omics clocks were developed for the mouse, however, extensive profiling the age of human cells is still lacking. To fill this gap, here we use available scRNA-seq data of 1,058,909 blood cells of 508 healthy, human donors (between 19 and 75 years), for developing single-cell transcriptomic clocks and predicting the age of human blood cells. By the application of the proposed cell-type-specific single-cell clocks, our main observations are that (i) transcriptomic age is associated with cellular senescence; (ii) the transcriptomic age of classical monocytes as well as naive B and T cells is decreased in moderate COVID-19 followed by an increase for some cell types in severe COVID-19; and (iii) the human embryo cells transcriptomically rejuvenated at the morulae and blastocyst stages. In summary, here we demonstrate that single-cell transcriptomic clocks are useful tools to investigate aging and rejuvenation at the single-cell level.

DOI: https://doi.org/10.1038/s42003-024-07094-5
Exp Physiol. 2024 Oct 28.

Ageing leads to selective type II myofibre deterioration and denervation independent of reinnervative capacity in human skeletal muscle.

Oscar Horwath, Marcus Moberg, Sebastian Edman, Andrew Philp, William Apró.

  Age-related loss of muscle mass and function is underpinned by changes at the myocellular level. However, our understanding of the aged muscle phenotype might be confounded by factors secondary to ageing per se, such as inactivity and adiposity. Here, using healthy, lean, recreationally active, older men, we investigated the impact of ageing on myocellular properties in skeletal muscle. Muscle biopsies were obtained from young men (22 ± 3 years, n = 10) and older men (69 ± 3 years, n = 11) matched for health status, activity level and body mass index. Immunofluorescence was used to assess myofibre composition, morphology (size and shape), capillarization, the content of satellite cells and myonuclei, the spatial relationship between satellite cells and capillaries, denervation and myofibre grouping. Compared with young muscle, aged muscle contained 53% more type I myofibres, in addition to smaller (-32%) and misshapen (3%) type II myofibres (P < 0.05). Aged muscle manifested fewer capillaries (-29%) and satellite cells (-38%) surrounding type II myofibres (P < 0.05); however, the spatial relationship between these two remained intact. The proportion of denervated myofibres was ∼2.6-fold higher in old than young muscle (P < 0.05). Aged muscle had more grouped type I myofibres (∼18-fold), primarily driven by increased size of existing groups rather than increased group frequency (P < 0.05). Aged muscle displayed selective deterioration of type II myofibres alongside increased denervation and myofibre grouping. These data are key to understanding the cellular basis of age-related muscle decline and reveal a pressing need to fine-tune strategies to preserve type II myofibres and innervation status in ageing populations.

Keywords:  NCAM; Pax7; ageing; human skeletal muscle; sarcopenia

DOI:  https://doi.org/10.1113/EP092222
J Physiol. 2024 Oct 28.

Neuromuscular mechanisms for the fast decline in rate of force development with muscle disuse - a narrative review.

Luca Ruggiero, Markus Gruber.

  The removal of skeletal muscle tension (unloading or disuse) is followed by many changes in the neuromuscular system, including muscle atrophy and loss of isometric maximal strength (measured by maximal force, Fmax). Explosive strength, i.e. the ability to develop the highest force in the shortest possible time, to maximise rate of force development (RFD), is a fundamental neuromuscular capability, often more functionally relevant than maximal muscle strength. In the present review, we discuss data from studies that looked at the effect of muscle unloading on isometric maximal versus explosive strength. We present evidence that muscle unloading yields a greater decline in explosive relative to maximal strength. The longer the unloading duration, the smaller the difference between the decline in the two measures. Potential mechanisms that may explain the greater decline in measures of RFD relative to Fmax after unloading are higher recruitment thresholds and lower firing rates of motor units, slower twitch kinetics, impaired excitation-contraction coupling, and decreased tendon stiffness. Using a Hill-type force model, we showed that this ensemble of adaptations minimises the loss of force production at submaximal contraction intensities, at the expense of a disproportionately lower RFD. With regard to the high functional relevance of RFD on one hand, and the boosted detrimental effects of inactivity on RFD on the other hand, it seems crucial to implement specific exercises targeting explosive strength in populations that experience muscle disuse over a longer time.

Keywords:  bed rest; explosive strength; limb immobilisation; muscle disuse; rate of force development; unilateral lower limb suspension; unloading

DOI:  https://doi.org/10.1113/JP285667
BMC Immunol. 2024 Oct 26. 25(1): 72

Chemokine CCL2 and its receptor CCR2 in different age groups of patients with COVID-19.

Vahid Bagheri, Hossein Khorramdelazad, Mehdi Kafi, Mitra Abbasifard.

   BACKGROUND: Despite the development of various antiviral drugs, most of them are not effective in the treatment of coronavirus disease 2019 (COVID-19) as a hyperinflammatory disorder. Chemokine (C-C motif) ligand 2 (CCL2) is one of the critical CC chemokines involved in the pathogenesis and severity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This study aimed to investigate the expression of CCL2 and CC chemokine receptor 2 (CCR2) in COVID-19 patients.
METHODS: Peripheral blood samples were collected from 60 confirmed COVID-19 patients and 60 age-matched healthy subjects. The ages of the subjects were categorized as follows: up to 20 years, 20 to 40 years, 40 to 60 years, and more than 60 years. CCL2 serum levels were measured using the enzyme-linked immunosorbent assay (ELISA). CCR2 gene expression in peripheral blood mononuclear cells (PBMCs) was measured employing real-time polymerase chain reaction (PCR).
RESULTS: In all age groups, CCL2 serum levels were significantly elevated in patients compared to healthy controls (P < 0.0001). CCL2 levels were higher in severe patients than in moderate patients. Moreover, CCR2 expression by PBMCs was higher in patients compared to control subjects. However, a significant difference between patients and controls over 60 years of age was identified (P = 0.0353). There was no significant difference in CCR2 expression between moderate and severe COVID-19 patients.
CONCLUSIONS: Taken together, the findings demonstrate that CCL2 and CCR2 are upregulated in COVID-19 patients at protein and mRNA levels, respectively. Therefore, the CCL2/CCR2 axis may be a potential therapeutic target in order to improve patient outcomes.

Keywords:  CCL2; CCR2; COVID-19; Chemokine; SARS-CoV-2 infection

DOI:  https://doi.org/10.1186/s12865-024-00662-8