bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–06–08
seven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Haptoglobin and Glutamine Synthetase May Biomark Cachexia Induced by Antiacute Myeloid Leukaemia Chemotherapy.
  2. A human skeletal muscle cross-bridge model to characterize the role of metabolite accumulation in muscle fatigue.
  3. Efficacy of Mitochondrial Transfer in Healing Toxin-Induced Damage to Neuromuscular Junction, an Empirical Study.
  4. Mitochondria-centred metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism.
  5. In vitro and in vivo muscle mass and strength during the first week of critical illness.
  6. Acute mitochondrial reactive oxygen species emissions drive mitochondrial dysfunction after traumatic muscle injury in male mice.
  7. Diverse effects of coexpression of human SOD1 variants on motor neuron disease.
  1. J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13849
    Haptoglobin and Glutamine Synthetase May Biomark Cachexia Induced by Antiacute Myeloid Leukaemia Chemotherapy.
    Dean G Campelj, Cara A Timpani, Guinevere Spiesberger, Luke E Formosa, Joel R Steele, Haijian Zhang, Ralf B Schittenhelm, Lewis Leow, Craig A Goodman, Emma Rybalka.
       BACKGROUND: Anticancer chemotherapy is an underappreciated contributor to cancer cachexia, an often-irreversible body-wasting condition that causes 20%-30% of cancer-related deaths. An obstacle to predicting, monitoring and understanding the mechanisms underlying chemotherapy cachexia is that each cancer (and subtype) is assigned different chemotherapeutic compounds, typically in multiagent regimens. Here, we investigate the chemotherapy induction regimen (CIR) used in the haematological cancer, acute myeloid leukaemia (AML). We hypothesised that the AML CIR would induce cachexia, including loss of lean tissue mass and skeletal muscle atrophy.
    METHODS: Using an unbiased proteomics approach, we interrogated the underlying molecular mechanisms. Three-month-old male Balb/c mice were treated with the AML CIR via intraperitoneal injections of daunorubicin (1.7 mg/kg) on Days 1-3 and cytarabine (33.2 mg/kg) administered on Days 1-7 or vehicle. Mice were assessed 24 h after the last treatment, on Day 8, or allowed to recover for 2 weeks and assessed on Day 22. A third cohort was given access to running wheels in cages. We assessed body composition and whole-body metabolism and assessed the muscle proteome using quantitative tandem mass tag labelling LC-MS/MS analysis. Data are available via ProteomeXchange with identifier PXD063910.
    RESULTS: The AML CIR-induced acute cachexia involved a ~10% loss of body mass, ~10% loss of lean mass and ~20% reduction in skeletal muscle fibre size. Whole-body metabolism and ambulatory activity declined. This cachexic phenotype did not recover over the 2-week post-CIR period (lean mass loss post-CIR: 1 week ~7% vs. 2 weeks ~9%). In voluntarily active CIR-treated mice, body wasting was exacerbated due to unchecked loss of fat mass (CIR sedentary: ~31% vs. CIR active: ~51%). Muscle proteome studies revealed upregulation of haptoglobin (Hp) and glutamine synthetase (Glul), which were positively correlated with body and lean mass loss. Hp was sensitive to the conditional induction, recovery and exacerbation of AML CIR-mediated cachexia, suggestive of biomarker potential.
    CONCLUSIONS: The AML CIR induces an acute reduction of body, lean and fat mass underpinned by skeletal muscle atrophy, hypermetabolism and catabolism. Our data uncovered a conditionally sensitive muscle biomarker in Hp, which may be useful as a prognostic tool across other scenarios of chemotherapy-induced myopathy and cachexia or as a target for therapeutic discovery in follow-up studies.
    Keywords:  anticancer chemotherapy; atrophy; biomarkers; cachexia; haptoglobin; skeletal muscle wasting
    DOI:  https://doi.org/10.1002/jcsm.13849
  2. Exp Physiol. 2025 May 31.
    A human skeletal muscle cross-bridge model to characterize the role of metabolite accumulation in muscle fatigue.
    John I Hendry, Muhammet Enes Erol, Gwenael Layec, Edward P Debold, Shivendra G Tewari, Anders Wallqvist, Venkat R Pannala.
      Skeletal muscle fatigue is accompanied by the accumulation of metabolites, such as adenosine diphosphate (ADP), inorganic phosphate (Pi), and protons (H+). However, we lack a comprehensive understanding of the contribution of these metabolic changes to the development of muscle fatigue during intense exercise and the underlying mechanisms. To address this gap, we collected data from young adults performing a dynamic (0.75 Hz) plantar flexion exercise to task failure (642 ± 104 s), including in vivo concentrations of metabolites and H+ measured by 31P magnetic resonance spectroscopy as well as muscle activation signals obtained via electromyography. Using these data, we developed and validated a human skeletal muscle model. Our model-based simulations suggested that to continue the plantar flexion exercise at the required power output, muscle activation should progressively increase. In the absence of this increased activation, we observed a reduction in force-generating capacity due to metabolite-mediated inhibition of actin-myosin cross-bridge cycling. Our simulations also showed that Pi reduced force production by 30% when we increased it 50% above the concentrations measured experimentally. A parameter sensitivity analysis suggested that force generation is strongly dependent on the rate of Pi release from the actin-myosin complex, and Pi inhibits force by increasing the rate of actin-myosin detachment. In addition, we proposed an alternative mechanism through which H+ might reduce muscle force generation during exercise. In contrast, elevated ADP levels did not significantly affect force generation. This study provides insight into the impact of metabolite accumulation on force generation and muscle fatigue development.
    Keywords:  cross‐bridge cycle; muscle force generation; musculoskeletal modelling; plantar flexion; skeletal muscle fatigue
    DOI:  https://doi.org/10.1113/EP092843
  3. Synapse. 2025 Jul;79(4): e70022
    Efficacy of Mitochondrial Transfer in Healing Toxin-Induced Damage to Neuromuscular Junction, an Empirical Study.
    Michael R Deschenes, Max Rackley, Sophie Fernandez, Megan Heidebrecht, Kate Hamilton, Hector G Paez, Christopher R Paez, Stephen E Alway.
      Neuromuscular diseases and damage affect many people of all ages and are responsible for an exorbitant medical cost, more than $200 million annually. Accordingly, finding an appropriate model to investigate potential curative interventions is necessary. One currently used involves the application of toxic agents on skeletal muscle followed by mitochondrial transplant therapy. A question regarding this model is whether such toxins impact not only muscle tissue but also the neuromuscular junctions (NMJs) responsible for exciting the muscle tissue. This question was addressed here by forming four experimental groups of C57BL/six mice (10-14 per group) that were 8-12 weeks of age: 1) controls whose muscles had not been injured or treated, 2) muscles taken from mice that were injured and then treated with mitochondrial supplement, 3) muscles that had not been injured but were still treated with mitochondria, and 4) muscles that were injured and received no mitochondrial treatment. Several pre- and postsynaptic features of NMJs were subject to immunofluorescent staining procedures before having morphological features assessed with confocal microscopy. Results revealed that only postsynaptic acetylcholine (ACh) receptors showed any significant (p < 0.05) between-group differences, including decreased area size and perimeter length around ACh receptor clusters in injured NMJs. However, presynaptic nerve terminal branching was not different (p > 0.05) among treatment groups, and structural features were not different between groups with the exception of dispersion of postsynaptic receptors. Overall, these results suggest that skeletal muscles damaged with toxin accurately mimic what occurs during toxin-induced damage and post-injury recovery and can be used as a faithful model of occurrences during damage to NMJs as a result of muscle damage along with recovery from that insult.
    Keywords:  bungarotoxin; confocal; myofiber; synapse
    DOI:  https://doi.org/10.1002/syn.70022
  4. Ann Rheum Dis. 2025 May 30. pii: S0003-4967(25)00961-6. [Epub ahead of print]
    Mitochondria-centred metabolomic map of inclusion body myositis: sex-specific alterations in central carbon metabolism.
    Elie Naddaf, Ibrahim Shammas, Surendra Dasari, Xuan-Mai T Petterson, Wolfdieter Springer, Eugenia Trushina, Ian R Lanza.
       OBJECTIVES: To benchmark metabolomic signatures of inclusion body myositis (IBM) in muscle tissue, highlighting sex-specific differences and the correlation with clinical parameters.
    METHODS: A total of 37 IBM patients and 22 controls without myopathy were included. All participants had bulk RNA sequencing performed previously. Clinical parameters included disease duration and manual muscle test (MMT) scores. Discovery metabolite screening and quantitative targeted metabolomics platforms were used. Levels of metabolites and RNA-metabolomic integrated modules were correlated with clinical parameters and the mitophagy marker, p-S65-Ubiquitin (p-S65-Ub).
    RESULTS: IBM muscle samples showed elevated citric acid (TCA) cycle intermediates and anaplerotic amino acids. Proximal glycolytic intermediates were decreased, while pentose phosphate pathway (PPP) metabolites were increased. Short-chain acylcarnitines were lower in IBM males but not in females. Lastly, nucleic acid bases were increased, and nucleotides were decreased. MMT correlated with PPP metabolites and nucleic acid bases, and inversely correlated with glycolysis metabolites and mono/diphosphate nucleotides. MMT also correlated with several amino acids, including cysteine, taurine, carnosine, and sarcosine. Acylcarnitines correlated with disease duration only in males. Four RNA-metabolomic integrated modules demonstrated significant correlations. The strongest correlations were observed between the pink module and both sexes and p-S65-Ub. MMT and p-S65-Ub correlated with 3 and 2 modules, respectively. The enriched pathways were related to central carbon metabolism, cytokine/chemokine signalling, neurotransmission, and mitogen-activated protein kinase (MAPK)/RAS signalling. Males had relatively similar correlations to the combined-sex analysis, while females had no significant correlation with any module.
    CONCLUSIONS: IBM is associated with clinically significant alterations in central carbon metabolism, with the strongest RNA-metabolomic-clinical correlations observed in males. Further research is needed to explore the role of these metabolic changes in IBM pathogenesis and their progression over time.
    DOI:  https://doi.org/10.1016/j.ard.2025.05.003
  5. Intensive Care Med Exp. 2025 Jun 03. 13(1): 57
    In vitro and in vivo muscle mass and strength during the first week of critical illness.
    Wout J Claassen, Isabel M van Ruijven, Marloes van den Berg, Rianne J Baelde, Alexcia Fortes Monteiro, Rajvi M N Balesar, Sylvia W Hania, Donald L van der Peet, Peter J M Weijs, Coen A C Ottenheijm, Sandra N Stapel.
       BACKGROUND: Loss of muscle mass and strength is provoked by critical illness. Our primary aim was to study the development of muscle atrophy and weakness in vitro in isolated myofibers and in vivo muscle mass and in vitro muscle strength during the first week of critical illness. Furthermore, we explored how in vitro muscle strength compares to healthy controls. Finally, we studied correlations between in vitro muscle mass and strength and in vivo muscle mass in critically ill patients.
    METHODS: We performed a secondary analysis using data from a randomized controlled trial. We studied contractile force of single myofibers isolated from muscle biopsies around admission (day 1-3) and around 1 week after inclusion (day 8-10). Furthermore, we studied myofiber cross-sectional area (CSA), proportion of fast-twitch myofibers, bio-electrical impedance analysis-derived fat-free mass index (FFMI), ultrasound-derived quadriceps muscle layer thickness (QMLT) and diaphragm thickness. In the control group, only contractile force outcomes were available.
    RESULTS: In total, ten ICU patients had two muscle biopsies taken. Maximum force of both fast and slow-twitch myofibers was reduced at day 8-10 compared to day 1-3, even though there were no differences in normalized force and calcium sensitivity. FFM and QMLT did not change over time, nor were there differences between groups. Compared to healthy controls, maximum force of myofibers was lower in the ICU group at day 8-10 in both slow and fast-twitch myofibers, while the calcium sensitivity of force was lower in slow-twitch myofibers. We found a significant correlation between myofiber CSA vs. FFMI (r = 0.68) and maximum force of the fast-twitch fibers vs. QMLT (r = 0.72).
    CONCLUSIONS: During the first week of critical illness, maximum force declined over time, while no other in vitro parameters changed. We found a moderate correlation between myofiber CSA vs. FFMI and maximum force of the fast-twitch fibers vs. QMLT.
    Keywords:  ICU; Muscle mass; Muscle strength
    DOI:  https://doi.org/10.1186/s40635-025-00755-7
  6. Am J Physiol Cell Physiol. 2025 Jun 04.
    Acute mitochondrial reactive oxygen species emissions drive mitochondrial dysfunction after traumatic muscle injury in male mice.
    Junwon Heo, David L Miller, Jessica R Hoffman, Emma Oberholtzer, Katelyn M Castelli, Genevieve C Sparagna, Kelsey H Fisher-Wellman, Sarah M Greising, Jarrod A Call.
      Volumetric muscle loss (VML) is characterized by contractile weakness, dysfunctional mitochondrial bioenergetics, and poor rehabilitation plasticity. A hyperpolarized mitochondrial membrane potential is one attribute of the dysfunction bioenergetics and can lead to excessive reactive oxygen species (ROS) emissions. The primary objective of this study was to define the role of acute ROS emissions after VML injury. Male C57BL/6J mice were randomized into experimental and control groups. A time course of ROS emissions and antioxidant buffering capacity (AoxBC) for VML-injured muscles was established across the first 60-days post-injury (dpi). SS-31, a mitochondrial-targeted peptide, was administered s.c. (8mg/kg/d) for up-to 14-dpi and specific electron transport chain complex ROS emissions and mitochondrial bioenergetics were investigated. SS-31 and wheel running were combined in a regenerative rehabilitation model to determine if attenuating acute ROS emissions improved adaptive capability of the remaining muscle. Lipidomic and proteomic analyses were conducted to explore mechanisms of SS-31 benefit after VML. ROS emissions were greater and AoxBC less during the first 14-dpi and this was associated with dysfunctional mitochondrial bioenergetics regardless of carbohydrate or fat fuel substrate. Complexes I, II, and III were identified as the primary sources of ROS emissions. SS-31 attenuated ROS emissions at both 7- and 14-dpi and led to greater mitochondrial respiratory conductance and efficiency out to 30-dpi. Regenerative rehabilitation did not produce greater contractile adaptations, but there was modest evidence of greater metabolic adaptations compared to rehabilitation alone. Lipidomic and proteomic analyses suggest that SS-31 contributes to redox protein abundance alterations after VML injury.
    Keywords:  Antioxidants; Muscle Metabolism; Redox Biology; Rehabilitation; elamipretide
    DOI:  https://doi.org/10.1152/ajpcell.00407.2025
  7. Hum Mol Genet. 2025 Jun 01. pii: ddaf088. [Epub ahead of print]
    Diverse effects of coexpression of human SOD1 variants on motor neuron disease.
    Eiichi Tokuda, Laura Leykam, Per Zetterström, Thomas Brännström, Peter M Andersen, Stefan L Marklund.
      Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most common mutation, D90A, disease can develop in both homozygous and, more rarely, in heterozygous individuals with unexplained differences in clinical presentation. There is mounting evidence that prion-like spread of SOD1 aggregation is the primary cause of the disease. Two different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and hSOD1WT, whereas hSOD1D90A transgenic mice form a distinct strain B in addition to A. To explore the effects of aggregate strain propensities when hSOD1 variants are coexpressed, we generated digenic hSOD1G85R/WT and hSOD1G85R/D90A mice. Coexpression of hSOD1WT considerably shortened the lifespan of hSOD1G85R mice to the extent expected from the neurotoxicities of the variants alone. In contrast, coexpression of hSOD1D90A had a minimal effect on survival, far smaller than expected. Moreover, time from onset to the end stage was markedly prolonged in the hSOD1G85R/D90A mice. Aggregation of hSOD1 developed concomitantly with motor neuron disease, and the aggregates contained large amounts of both coexpressed variants in both digenic models. Our findings suggest that hSOD1WT has high a capacity to coaggregate with mutants and enhance neurotoxicity. Such interactions may be restricted by differences in strain propensities, which may contribute to the primarily recessive inheritance associated with the hSOD1D90A mutation.
    Keywords:  Aggregate strains; Bladder control impairment; Coexpression; Strain selection; Superoxide dismutase-1
    DOI:  https://doi.org/10.1093/hmg/ddaf088
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