bims-musmir 2025-06-15 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–06–15
seventeen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Muscle Mitochondrial Respiration and Cardiorespiratory Fitness Contribute to Slower Walking Speed of Older Individuals Who Identify as Black.
Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism.
Impact of sarcopenia and obesity on skeletal muscle size, gene expression, and mitochondrial function.
Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis.
Early endosome disturbance and endolysosomal pathway dysfunction in Duchenne muscular dystrophy.
Extensive differential gene expression and regulation by sex in human skeletal muscle.
Altered muscle transcriptome as molecular basis of long-term muscle weakness in survivors from critical illness.
miR-320-3p regulates apelin and TGF-β/SMAD3 signaling in hypobaric hypoxia exposed rats to induce skeletal muscle atrophy.
The emerging role of miRNAs in biological aging and age-related diseases.
Effects of Low Load Blood-Flow-Restriction Training on Body Composition and Strength in Cancer Cachexia: A Case Study.
The SUV39 Family of H3K9 Methyltransferases in Skeletal Muscle Stem Cells.
Neurophysiology and muscle histopathology in ICU-acquired muscle weakness: Lessons learned from COVID-19.
Patients Having Major Abdominal Cancer Surgery Exhibit Significant Acute Muscle Wasting.
Predicting amyotrophic lateral sclerosis in the pre-symptomatic phase: Insights from SOD1G93A mouse gene expression profiles.
Association of cardiorespiratory fitness with HR-pQCT bone parameters in older adults: the Study of Muscle, Mobility and Aging (SOMMA).
COVID-19 induces persistent transcriptional changes in adipose tissue that are not associated with Long COVID.

Aging Cell. 2025 Jun;24(6): e70040

Muscle Mitochondrial Respiration and Cardiorespiratory Fitness Contribute to Slower Walking Speed of Older Individuals Who Identify as Black.

Paul M Coen, Fanchao Yi, Li-Yung Lui, Giovanna Distefano, Sofhia V Ramos, Bret H Goodpaster, Peggy M Cawthon, Russell T Hepple, Stephen B Kritchevsky, Steven R Cummings, Gregory J Tranah, Anne B Newman, James P DeLany.

  In the United States, older adults who self-identify as Black have a disproportionately higher incidence of mobility disability compared to those who are White. Whether older adults who are Black also have lower fitness and mitochondrial energetics has not been adequately investigated. The study of muscle, mobility and aging (SOMMA) examined 879 participants aged ≥ 70 years old, including 116 who self-identified as Black. Mitochondrial respiration (Max OXPHOS) was measured in permeabilized fibers from muscle biopsies. Cardiorespiratory fitness (VO2 peak) was determined by a cardiopulmonary exercise test. Education, income, financial resources, race, sex, and age were determined by self-report. We used propensity score matching to match Blacks with Whites with a 1:1 ratio. Black (n = 90) and White (n = 90) groups were matched for age, sex, SOMMA multimorbidity index, BMI, muscle mass, physical activity, marital status, educational achievement, and whether financial needs were met (all p > 0.05). Despite being well matched for these variables, those who identified as Black had a slower 400-m walking speed (0.97 vs. 1.03 m/s, p = 0.014), lower Max OXPHOS (50.8 vs. 60.9 (pmol/(s*mg)), p = 0.0002), and lower cardiorespiratory fitness (1391 vs. 1566 mL/min, p = 0.007) when compared to those who identified as White. Multivariate regression showed that VO2 peak and Max OXPHOS, but not socioeconomic factors, attenuated the race difference in 400-m walking speed. In conclusion, while the etiology of race differences in mobility is multifactorial, our data indicate that muscle mitochondrial respiration and cardiorespiratory fitness may contribute to the slower walking speed of individuals who identify as Black compared to White.

Keywords:  aging; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1111/acel.70040
Life Metab. 2025 Jun;4(3): loaf012

Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.

Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.

  Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have consistently high, while others show consistently low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mitochondrial DNA (mtDNA) density was correlated between tissues (median r = -0.01 to 0.16), indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues. Similarly, RNA sequencing (RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men (genotype-tissue expression [GTEx]) showed only small to moderate coherence between some tissues, such as between brain regions (r = 0.26), but not between brain-body tissue pairs (r = 0.01). The mtDNA copy number (mtDNAcn) also lacked coherence across human tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were partially attributable to (i) tissue-specific activation of energy sensing pathways, including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the integrated stress response (ISR), and other molecular regulators of mitochondrial biology, and (ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes. These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.

Keywords:  disease risk; energy sensing; gene regulation; inter-organ crosstalk; mitochondrial biogenesis; mitochondrion

DOI:  https://doi.org/10.1093/lifemeta/loaf012
Mol Metab. 2025 Jun 07. pii: S2212-8778(25)00089-4. [Epub ahead of print] 102182

microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism.

Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Kevin A Murach, Kelsey H Fisher-Wellman, Ryan L Boudreau, Yuan Wen, John J McCarthy.

  Metabolic flexibility refers to the ability of a tissue to adjust cellular fuel choice in response to conditional changes in metabolic demand and activity. A loss of metabolic flexibility is now recognized as a defining feature of various diseases and cellular dysfunction. In this study, using an inducible, skeletal muscle-specific knockout (KO) mouse, we found microRNA-1 (miR-1), the most abundant microRNA (miRNA) in skeletal muscle, was necessary to maintain whole-body metabolic flexibility. This was demonstrated by a loss of diurnal oscillations in whole-body respiratory exchange ratio and higher fasting blood glucose in miR-1 KO mice. Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) and RNA-seq analyses identified, for the first time, bona fide miR-1 target genes in adult skeletal muscle that regulated pyruvate metabolism. Comprehensive bioenergetic phenotyping combined with skeletal muscle proteomics and metabolomics showed that miR-1 was necessary to maintain metabolic flexibility by regulating pyruvate metabolism through mechanisms including the alternative splicing of pyruvate kinase (Pkm). The loss of metabolic flexibility in the miR-1 KO mouse was rescued by pharmacological inhibition of the miR-1 target, monocarboxylate transporter 4 (MCT4), which redirects glycolytic carbon flux toward oxidation. The maintenance of metabolic flexibility by miR-1 was necessary for sustained endurance activity in mice and in C. elegans. The physiological down-regulation of miR-1 in response to a hypertrophic stimulus in both humans and mice caused a similar metabolic reprogramming necessary for muscle cell growth. Taken together, these data identify a novel post-transcriptional mechanism of whole-body metabolism regulation mediated by a tissue-specific miRNA.

Keywords:  MCT4; PKM; VB124; aerobic glycolysis; eCLIP-seq; resistance training

DOI:  https://doi.org/10.1016/j.molmet.2025.102182
Geroscience. 2025 Jun 12.

Impact of sarcopenia and obesity on skeletal muscle size, gene expression, and mitochondrial function.

Hector G Paez, Christopher R Pitzer, Jessica L Halle, Peter J Ferrandi, James A Carson, Junaith S Mohamed, Stephen E Alway.

  Skeletal muscle is a primary tissue of dysfunction during both aging and obesity. Recently, the coincidence of obesity and aging has gained attention due to the intersection of the obesity epidemic with an aging demographic. Both aging and obesity are associated with marked defects in skeletal muscle metabolic health. Despite these findings, we have a poor understanding of how obesity and aging may interact to impact skeletal muscle mass and metabolic health. Therefore, we investigated the impact of high-fat diet (HFD)-induced obesity on skeletal muscle mass, mitochondrial function, transcriptomics, and whole-body metabolism in young and aged mice. We observed main effects of diet and age on several measures of whole-body metabolic function (VO2, VCO2, and RER). Complex I-driven mitochondrial proton leak was significantly elevated by HFD-induced obesity across both age groups; however, a main effect of aging for reduced complex I leak was detected in the soleus muscle. Interestingly, aged animals fed a HFD did not exhibit lower muscle mass than chow-fed young animals, but did present with stark increases in muscle triglyceride content and a unique transcriptional response to HFD. HFD-induced obesity impacted the muscle transcriptome differently in the muscles of young and aged mice, indicating that obesity can change altered gene expression with age. Our findings suggest that the presence of obesity can both compound and counteract age-associated changes to muscle mass, gene expression, and mitochondrial function.

Keywords:  Aging; Metabolism; Mitochondria; Obesity; Sarcopenic obesity; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-025-01726-2
bioRxiv. 2025 Jun 07. pii: 2025.06.03.657464. [Epub ahead of print]

Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis.

Nikita Bhalerao, Yamini Ogoti, Jessica Peura, Calvin Johnson, Qingbo Chen, Ekaterina D Korobkina, Faith N Keller, Maximilian Wengyn, Robert J Norgard, Claire Shamber, Kelsey Klute, Dominick DiMaio, Karine Sellin, Paul M Grandgenett, Rui Li, Michael A Hollingsworth, Adilson Guilherme, Michael P Czech, Richard Kremer, Lihua Julie Zhu, Emma V Watson, Marcus Ruscetti, David A Guertin, Jason R Pitarresi.

Pancreatic cancer patients have the highest rates and most severe forms of cancer cachexia, yet cachexia etiologies remain largely elusive, leading to a lack of effective intervening therapies. PTHrP has been clinically implicated as a putative regulator of cachexia, with serum PTHrP levels correlating with increased weight loss in PDAC patients. Here we show that cachectic PDAC patients have high expression of tumor PTHrP and use a genetically engineered mouse model to functionally demonstrate that deletion of Pthlh (encoding the PTHrP protein) blocks cachectic wasting, dramatically extending overall survival. The re-expression of PTHrP in lowly cachectic models is sufficient to induce wasting and reduce survival in mice, which is reversed by the conditional deletion of the PTHrP receptor, Pth1r , in adipocytes. Mechanistically, tumor-derived PTHrP suppresses de novo lipogenesis in adipocytes, leading to a molecular rewiring of adipose depots to promote wasting in the cachectic state. Finally, the pharmacological disruption of the PTHrP-PTH1R signaling axis abrogates wasting, highlighting that a targeted disruption of tumor-adipose crosstalk is an effective means to limit cachexia.
STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is the prototypical cancer type associated with cancer cachexia, a debilitating wasting syndrome marked by adipose tissue loss and muscle atrophy. Herein, we establish that PTHrP is a tumor-derived factor that facilitates cachexia by downregulating de novo lipogenesis in adipocytes and that blocking PTHrP is an effective means to limit wasting in preclinical mouse models.

DOI: https://doi.org/10.1101/2025.06.03.657464
Am J Pathol. 2025 Jun 09. pii: S0002-9440(25)00189-0. [Epub ahead of print]

Early endosome disturbance and endolysosomal pathway dysfunction in Duchenne muscular dystrophy.

Julie Chassagne, Nathalie Da Silva, Ines Akrouf, Bruno Cadot, Laura Julien, Ines Barthélémy, Stéphane Blot, Caroline Le Guiner, Mai Thao Bui, Norma B Romero, Jeanne Lainé, France Pietri-Rouxel, Pierre Meunier, Kamel Mamchaoui, Stéphanie Lorain, Marc Bitoun, Sofia Benkhelifa-Ziyyat.

Duchenne muscular dystrophy (DMD) is a lethal dystrophy characterized by the progressive loss of muscle fibers caused by mutations in DMD gene and absence of the dystrophin protein. While autophagy and lysosome biogenesis defects have been described in DMD muscles, the endosomal pathway has never been studied. Here, we showed that impaired lysosome formation is associated with altered acidification and reduced degradative function of the endolysosomal pathway in muscle cells derived from DMD patients. Our data demonstrated that early endosomes are increased in these cells as well as in muscle biopsies from DMD patients and two animal models of DMD, mdx mice and GRMD dogs. We determined that these abnormalities are due to the lack of dystrophin per se and could be correlated with disease progression and severity. We further identified an abnormal upregulation of the Rab5 GTPase protein, one key actor of early endosomal biogenesis and fusion, in the three DMD models which may underlie the endosomal defects. Finally, we demonstrated that Rab5 knock-down in human DMD muscle cells as well as dystrophin restoration in GRMD dogs, normalize Rab5 expression levels and rescue endosomal abnormalities. This study unveils a defect in a pathway essential for muscle homeostasis and for the efficacy of DMD therapies.

DOI: https://doi.org/10.1016/j.ajpath.2025.05.007
Cell Genom. 2025 May 29. pii: S2666-979X(25)00171-5. [Epub ahead of print] 100915

Extensive differential gene expression and regulation by sex in human skeletal muscle.

Sarah C Hanks, Abigail S Mauger, Arushi Varshney, Dan L Ciotlos, Nandini Manickam, Narisu Narisu, Alexandria J Shumway, Peter Orchard, Michael R Erdos, Michael D Sweeney, Jeffrey Okamoto, Anne U Jackson, Heather M Stringham, Lori L Bonnycastle, Xiang Zhou, Timo A Lakka, Karen L Mohlke, Jaakko Tuomilehto, Markku Laakso, Michael Boehnke, Praveen Sethupathy, Francis S Collins, Heikki A Koistinen, Stephen C J Parker, Laura J Scott.

  The identification of sex-differential gene regulatory elements is essential for understanding sex-differential patterns of health and disease. We leveraged bulk and single-nucleus RNA sequencing (RNA-seq) and single-nucleus ATAC-seq data from 281 skeletal muscle biopsies to characterize sex differences in gene expression and regulation at the cell-type and whole-tissue levels. We found highly concordant sex-biased expression of over 2,100 genes across the three muscle fiber types and bulk tissue. Gene pathways related to mitochondrial activity and energy metabolism were enriched for male-biased expression, whereas those related to signal transduction and cell differentiation were enriched for female-biased expression. We found widespread sex-biased chromatin accessibility enriched in proximal and distal gene regulatory states; in gene promoters, sex-biased chromatin accessibility was positively associated with sex-biased expression. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) also showed extensive sex-biased expression in the fiber-type and bulk data, respectively. Together, these results highlight nuclear and cytoplasmic mechanisms for sex-differential gene regulation in skeletal muscle.

Keywords:  chromatin accessibility; gene expression; gene regulation; miRNA; sex differences; single nucleus; skeletal muscle; snATAC-seq; snRNA-seq

DOI:  https://doi.org/10.1016/j.xgen.2025.100915
Intensive Care Med. 2025 Jun 10.

Altered muscle transcriptome as molecular basis of long-term muscle weakness in survivors from critical illness.

Ceren Uzun Ayar, Fabian Güiza, Inge Derese, Lies Pauwels, Sarah Vander Perre, Isabel Pintelon, Michaël Casaer, Nathalie Van Aerde, Greet Hermans, Sarah Derde, Lucas Kreiss, Greet Van den Berghe, Ilse Vanhorebeek.

   PURPOSE: Critically ill patients requiring intensive care unit (ICU) admission suffer from muscle weakness that persists for years, compromising quality-of-life. The pathophysiology of this long-term weakness remains unclear. We hypothesized that former ICU-patients show a long-term abnormal RNA-expression profile, which may contribute to lower long-term strength and for which modifiable risk factors can be identified.
METHODS: This pre-planned secondary analysis of the EPaNIC-trial compared muscle transcriptomes of 115 former ICU-patients 5 years after critical illness and 30 matched controls with RNA-sequencing, followed by pathway over-representation and differential co-expression analyses of the differentially expressed RNAs. We used multivariable linear regression analyses to identify which of the abnormal RNA-expressions associated with the long-term muscle strength of the patients and to identify potential risk factors for the abnormal RNA-expressions.
RESULTS: In former patients, 234 down-regulated and 116 up-regulated RNAs were identified after adjustment for age, sex, and BMI. Pathway over-representation and further molecular and histological analyses indicated impaired mitochondrial energy metabolism, disturbed lipid metabolism, and increased collagen formation/fibrosis in former patients. Abnormal muscle RNA-expression in former patients correlated with lower long-term muscle strength. Several treatments given in-ICU and at 5-year follow-up associated with abnormal RNA-expression, most notably in-ICU early parenteral nutrition (early PN) and glucocorticoid use.
CONCLUSION: Abnormal RNA-expression profiles 5 years after critical illness suggest disrupted mitochondrial function, disturbed lipid metabolism, and fibrosis, associated with lower long-term muscle strength and partly attributable to possibly avoidable risk factors. These findings open perspectives for prevention and possibly treatment of long-term muscle weakness after critical illness.
TRIAL REGISTRATION NUMBER AND DATE: ClinicalTrials.gov-NCT00512122, July 31, 2007.

Keywords:  Critical illness; Intensive care unit; Mitochondria; Muscle weakness; Post-intensive care syndrome; Transcriptome

DOI:  https://doi.org/10.1007/s00134-025-07949-3
J Physiol Biochem. 2025 Jun 11.

miR-320-3p regulates apelin and TGF-β/SMAD3 signaling in hypobaric hypoxia exposed rats to induce skeletal muscle atrophy.

Samrita Mondal, Sukanya Srivastava, Swati Srivastava, Richa Rathor, Geetha Suryakumar.

  Emerging research on microRNA has decoded its crucial role in gene regulation, development and diseases. Skeletal muscle atrophy is reported in several chronic diseases as well as prolonged stay at high altitude. miR-320-3p is reported to be upregulated in various chronic diseases including cancer, heart diseases, diabetes, and chronic kidney diseases. The present study evaluates the role of miR-320-3p expression in regulating apelin and its downstream signaling under hypobaric hypoxia (HH) at high altitude. The expression of miR-320-3p was found to be upregulated during 7days HH (7DHH) exposure at 25,000 ft as compared to control group. The targets for miR-320-3p were retrieved from miRWalk 3.0, TargetScan 8.0, miRTarBase 10.0 databases in Rattus norvegicus. Using in silico approach, 26 myokines were screened out of total 14,435 targets of rno-miR-320-3p and levels of few myokines were experimentally validated. The expression of apelin, decorin, osteocrin, meteorin-like myokines were found to be significantly decreased while myostatin was significantly increased during HH exposure as compared to control rats. Enhanced expression of Tgfb and p-Smad3 under 7DHH indicated activation of protein degradation pathways. Expression of Pgc1a and Nrf2, the critical regulators of mitochondrial biogenesis, were significantly decreased under HH. Thus, increased expression of miR-320-3p regulate apelin and modulate downstream signaling via attenuation of mitochondrial biogenesis and myogenesis. Hence, miR-320-3p and myokines play pivotal role to regulate skeletal muscle atrophy. Further research on potential targets of miR-320-3p regulating the muscle mass may lead to the development of novel therapeutics in personalized medicine to combat skeletal muscle diseases.

Keywords:  Apelin; Atrophy; Skeletal muscle; Therapeutics; miR-320-3p; miRNA

DOI:  https://doi.org/10.1007/s13105-025-01100-y
Noncoding RNA Res. 2025 Aug;13 131-152

The emerging role of miRNAs in biological aging and age-related diseases.

Rawad Turko, Amro Hajja, Ahmad M Magableh, Mohammed H Omer, Areez Shafqat, Mohammad Imran Khan, Ahmed Yaqinuddin.

  Ageing is a complex biological process characterised by the accumulation of molecular and cellular damage leading to functional decline and an increased risk of chronic disease and geriatric syndromes. Despite data showing that lifestyle modifications, such as caloric restriction and exercise, can lead to healthy ageing and greatly reduce the incidence of chronic disorders, no medical therapies exist to delay or prevent these conditions effectively. We also lack tools to effectively track the ageing process in a manner that predicts an individual's risk of chronic disease and assess response to lifestyle or medical interventions. This review explores the emerging role of microRNAs (miRNAs), which are small non-coding RNAs that regulate gene expression, as a unifying mechanism underlying the biology of ageing and age-related conditions, including cardiovascular and neurodegenerative diseases, metabolic syndromes, musculoskeletal disorders such as sarcopenia, osteoarthritis and osteoporosis, and various cancers. We also examine the interactions of miRNAs with various hallmarks of ageing, such as DNA damage, cellular senescence, and mitochondrial dysfunction. We then explore the challenges of translating miRNA-based approaches from preclinical promise to clinical utility, emphasizing the need for trial-level validation to correlate miRNA profiles with clinically meaningful, patient-centred endpoints. By consolidating these findings, this article puts miRNAs forward as a pivotal mechanism in geroscience, offering a novel framework to mitigate ageing-related multimorbidity and bridge the gap between lifespan and healthspan.

Keywords:  Ageing; Aging; Biomarkers; Cancer; Neurodegeneration; miRNAs; microRNAs

DOI:  https://doi.org/10.1016/j.ncrna.2025.05.002
Med Sci Sports Exerc. 2025 Jun 09.

Effects of Low Load Blood-Flow-Restriction Training on Body Composition and Strength in Cancer Cachexia: A Case Study.

Frieder Krause, Nils Schaffrath, Ingeborg Rötzer, Jenny Hoffart, Michael Behringer, Elke Jäger, Katharina Graf.

   PURPOSE: A common side effect from cancer and anti-cancer treatment is cancer-associated cachexia (CAC), a multifactorial syndrome characterized by the loss of bodyweight, skeletal muscle and adipose tissue. Recommended therapeutic options are multidimensional, including nutritional, pharmacological and exercise interventions. A novel therapeutic approach is the use of low-load resistance training combined with blood-flow-restriction to the trained limbs (LL-BFR). It has been shown to induce adaptations in muscle mass and strength despite low training load in various clinical populations and might be a suitable training modality for cancer patients suffering from CAC.
METHODS: A 56-year-old female patient diagnosed with stage IV gallbladder cancer, suffering from CAC performed LL-BFR training twice weekly for twelve weeks and received a guideline-based nutritional intervention. All outcome measures (maximal strength (8-RM), handgrip strength, body mass, lean body mass, body cell mass, quality of life and symptom burden) were evaluated before and directly after the training period.
RESULTS: Adherence was moderate (67% of all training sessions completed) and no adverse events were noted. All measures of physical capacity and body composition improved between 19-55% and 9-11%, respectively. Quality of life decreased in 5/6 subscales while symptom burden increased in 2/4 subscales.
CONCLUSIONS: Treatment of CAC requires a multitargeted and interdisciplinary approach. This is the first case study using LL-BFR training in an oncological patient during active therapy. Our results show that LL-BFR was feasible and, despite no positive effect on quality of life and symptom burden, could induce relevant changes of muscle strength and muscle mass in a relatively short training period. Further research is necessary to confirm the results of this case study in randomised controlled trials.

Keywords:  BLOOD-FLOW-RESTRICTION; CACHEXIA; CANCER; CASE STUDY; EXERCISE

DOI:  https://doi.org/10.1249/MSS.0000000000003779
FASEB Bioadv. 2025 Jun;7(6): e70014

The SUV39 Family of H3K9 Methyltransferases in Skeletal Muscle Stem Cells.

Pauline Garcia, Slimane Ait-Si-Ali, Fabien Le Grand.

  Skeletal muscle repair is primarily driven by muscle stem cells (MuSCs) that regenerate damaged myofibers. The differentiation process of MuSCs into differentiated myofibers, known as adult myogenesis, is tightly regulated by various transcription factors, which involve precise spatio-temporal gene expression patterns. Epigenetic factors play an important role in this regulation, as they modulate gene expression to maintain the balance between the different myogenic states. Histone lysine methyltransferases KMT sare key epigenetic regulators, with the SUV39 family being of particular interest for their role in gene repression via H3K9 methylation. This family comprises SUV39H1, SUV39H2, SETDB1, SETDB2, G9A, and GLP. While the functions of SUV39 family members have been well characterized during development in embryonic stem cells and in disease contexts such as cancer, their functions in adult stem cell populations, especially in MuSCs, are still not fully understood. Recent studies shed new light on how the SUV39 family influences muscle biology, particularly in regulating MuSCs fate and adult myogenesis. These enzymes are critical for maintaining the epigenetic landscape essential for effective muscle repair, as they regulate the transition between different myogenic states and ensure coordinated gene expression during regeneration. Here, we present a comprehensive overview of the functions of the SUV39 KMTs family in skeletal muscle biology, emphasizing their role in adult myogenesis and exploring the broader implications for muscle regeneration and related diseases.

Keywords:  SUV39; gene repression; histone lysine methyltransferase; histone methylation; skeletal muscle

DOI:  https://doi.org/10.1096/fba.2024-00102
Clin Neurophysiol Pract. 2025 ;10 172-180

Neurophysiology and muscle histopathology in ICU-acquired muscle weakness: Lessons learned from COVID-19.

Eva K Hejbøl, Atle V Lomstein, Henrik D Schrøder, Benjamin Khan, Thomas Harbo, Hatice Tankisi.

   Objective: To describe different electrophysiological, histopathological, and ultrastructural patterns of muscle pathology in COVID-19-associated intensive care unit acquired weakness (ICUAW) and raise the question of whether COVID-19-associated critical illness myopathy (CIM) is a distinct entity or is similar to CIM of other causes.
Methods: A series of three patients with COVID-19-associated ICUAW were presented.Clinical examination, electrophysiological testing, and muscle pathology with light and electron microscopy were reported systematically.
Results: All three patients were clinically affected with severe proximal and distal weakness of upper and lower extremities, increased plasma levels of muscle enzymes, and had myopathic electromyography. Furthermore, in two patients, electrophysiological signs of inflammatory myopathy with profuse denervation activity were present. Muscle pathologies were prominent but very diverse. One patient had signs of CIM, another showed severe inflammatory myopathy, and the main finding in the third patient was mitochondrial changes.
Conclusion: Although the three cases showed similar clinical and electrophysiological patterns, muscle pathology revealed distinct underlying features. This spectrum of muscle disease among patients with severe COVID-19 includes CIM, autoimmune response to the COVID-19 infection, and mitochondrial dysfunction.
Significance: Electrophysiology and histopathology complement each other and are important for determining the etiology, as well as guiding treatment and prognosis.

Keywords:  COVID-19; Critical illness myopathy; Electromyography; Intensive care unit acquired weakness; Muscle biopsy

DOI:  https://doi.org/10.1016/j.cnp.2025.05.001
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13858

Patients Having Major Abdominal Cancer Surgery Exhibit Significant Acute Muscle Wasting.

Gabor Dudas, Ismita Chhetri, Martin Whyte, Margaret Rayman, Rachel Simmonds, Anthony Catchpole, Mark Griffiths, Ben Creagh-Brown.

   BACKGROUND: Postoperative myopenia (acute muscle loss) is a significant concern following major cancer resection surgery, contributing to prolonged recovery, increased dependency and impaired quality of life. Despite its clinical relevance, the mechanisms underlying postoperative myopenia and its potential mediators remain poorly understood. This study aims to evaluate the acute changes in muscle size, strength and activity following major cancer surgery and to explore the role of insulin resistance and selenium deficiency as potential mediators of these alterations.
METHODS: A prospective cohort study was conducted involving 52 patients undergoing elective open major abdominal surgery for cancer. Preoperative and postoperative assessments included measurements of rectus femoris cross-sectional area (RFCSA) via ultrasound, handgrip strength (HGS), sniff nasal inspiratory pressure (SNIP) and physical activity using an accelerometer. Blood samples were analysed for markers of muscle metabolism, systemic inflammation, insulin resistance and selenium levels. Statistical analyses were performed to compare preoperative and postoperative values and to explore correlations between these measures and clinical outcomes.
RESULTS: A significant reduction in RFCSA was observed in 50% of patients, with a median decrease of 10.2% within the first week post-surgery, which persisted at the 6-week follow-up. HGS and SNIP also showed significant declines postoperatively, and reduced physical activity was associated with greater muscle loss. Insulin resistance and postoperative selenium depletion were associated with greater reductions in RFCSA.
CONCLUSION: Major cancer surgery is associated with significant acute muscle loss, which is not fully recovered by 6 weeks postoperatively. Insulin resistance and selenium deficiency may contribute to this muscle loss. Further research is needed to investigate potential interventions to prevent or mitigate postoperative myopenia.

Keywords:  cancer surgery; insulin resistance; muscle loss; muscle wasting; myopenia; postoperative recovery

DOI:  https://doi.org/10.1002/jcsm.13858
Exp Neurol. 2025 Jun 06. pii: S0014-4886(25)00193-1. [Epub ahead of print]392 115329

Predicting amyotrophic lateral sclerosis in the pre-symptomatic phase: Insights from SOD1G93A mouse gene expression profiles.

Valentina La Cognata, Maria Guarnaccia, Giovanna Morello, Giulia Gentile, Sebastiano Cavallaro.

  Amyotrophic lateral sclerosis (ALS) is a fast-paced fatal disease that requires immediate intervention to slow down the course of pathology and improve patients' quality of life. However, in most cases, ALS is diagnosed too late. For this reason, an accurate diagnostic test is urgently needed to identify ALS patients early, enabling a timely introduction of novel therapeutics and effective monitoring of disease progression. To address this significant unmet medical need, we explored a transcriptome-based signature to predict ALS during the preclinical phase. Using publicly available gene expression profiles from central nervous system (lumbar isolated motor neurons and spinal cord homogenates) of transgenic SOD1G93A mice with different genetic background and their respective control littermates, covering pre-symptomatic to late stages of the disease, we identified 463 differentially expressed genes (DEGs), primarily involved in immune response and metabolic processes. Based on this ALS gene-associated signature, we tested three machine learning binary classifiers (Support Vector Machine, Neural Network and Linear Discriminant Analysis), which demonstrated highly significant predictive power in discriminating mutant SOD1G93A from controls mice, even at pre-symptomatic stages. This was evident in both the discovery cohort and in two additional peripheral cross-tissue validation datasets from preclinical SOD1G93A sciatic nerve and muscles. Our study provides the first proof of concept for early ALS detection using a machine learning-based transcriptomic classifier. This could lead to earlier diagnosis, potentially enabling effective monitoring of disease progression and earlier interventions.

Keywords:  ALS; Artificial intelligence; DEGs; Linear Discriminant Analysis (LDA); Machine learning; Neural Network (NN); Pre-symptomatic; Support Vector Machine (SVM); Transcriptomics

DOI:  https://doi.org/10.1016/j.expneurol.2025.115329
Osteoporos Int. 2025 Jun 12.

Association of cardiorespiratory fitness with HR-pQCT bone parameters in older adults: the Study of Muscle, Mobility and Aging (SOMMA).

Nina Z Heilmann, Kerri S Freeland, Reagan E Garcia, Nancy W Glynn, Lauren S Roe, Tong Yu, Nicole M Sekel, Kristen J Koltun, Katelyn I Guerriere, Julie M Hughes, Bradley C Nindl, Ashley A Weaver, Paolo Caserotti, Peggy M Cawthon, Paul M Coen, Anne B Newman, Jane A Cauley, Elsa S Strotmeyer.

  Higher cardiorespiratory fitness may be associated with better bone health in older age, though this has not been investigated using state-of-the-science VO2peak and HR-pQCT bone density, strength, and microarchitecture measures. We found that higher VO2peak associated with higher bone strength in men, but not women, which may inform fracture prevention interventions.
INTRODUCTION: Maintaining cardiorespiratory fitness among older adults holds potential benefits for bone health, though this association has not been investigated using gold-standard measures of VO2peak and state-of-the-science measures of bone density, strength, and microarchitecture.
METHODS: Participants included 123 men (age 76.2 ± 4.4 years, 93% White) and 188 women (age 76.1 ± 4.7 years, 87% White) in the Study of Muscle, Mobility and Aging (SOMMA). Absolute peak oxygen consumption (VO2peak) was measured from treadmill cardiopulmonary exercise testing using a modified Balke protocol at the baseline visit. High-resolution peripheral quantitative computed tomography (HR-pQCT) and dual-energy X-ray absorptiometry (DXA) scans were collected after the first annual follow-up visit (mean follow-up 1.2 ± 0.1 years) to assess radial and tibial bone microarchitecture and strength and hip areal bone mineral density (BMD), respectively. VO2peak and bone parameters were standardized within sex and analyses were stratified by sex. Linear regression models adjusted for age, race, weight, alcohol consumption, smoking, physical activity (wrist-worn accelerometry), multimorbidity index, arthritis, hypertension, and limb length (HR-pQCT parameters) or height (DXA parameters).
RESULTS: In men, higher VO2peak (per SD) was associated with higher tibial (standardized [std] β = 0.26, p = 0.03) and radial (std β = 0.36, p = 0.007) failure load, but not with DXA or other HR-pQCT bone parameters. No significant associations were found for women.
CONCLUSIONS: Associations of VO2peak with bone strength found in older men suggest VO2peak is associated with bone parameters in a sex-specific manner and mechanisms for these sex differences should be explored. Interventions aimed at increasing cardiorespiratory fitness should be evaluated for potential benefit to bone health among older men.

Keywords:  Aging; BMD; DXA; Fitness; HR-pQCT; VO2peak

DOI:  https://doi.org/10.1007/s00198-025-07485-2
bioRxiv. 2025 May 27. pii: 2025.05.23.655815. [Epub ahead of print]

COVID-19 induces persistent transcriptional changes in adipose tissue that are not associated with Long COVID.

Soneida DeLine-Caballero, Kalani Ratnasiri, Heping Chen, Seynt Jiro Sahagun, Uma M Mangalanathan, Trisha R Barnard, Nicole Turk, Jasmine Yang, Natesh Saini, Ekrem M Ayhan, Hasiyet Memetimin, Brian S Finlin, Zachary Leicht, Phillip A Kern, Ivette Emery, Brooke M Leeman, Gregory E Edelstein, Samantha Costa, Alina Choi, Jonathan Z Li, Clifford Rosen, Tracey McLaughlin, Catherine A Blish.

Long COVID is a heterogeneous condition characterized by a wide range of symptoms that persist for 90 days or more following SARS-CoV-2 infection. Now more than five years out from the onset of the SARS-CoV-2 pandemic, the mechanisms driving Long COVID are just beginning to be elucidated. Adipose tissue has been proposed as a potential reservoir for viral persistence and tissue dysfunction contributing to symptomology seen in Long COVID. To test this hypothesis, we analyzed subcutaneous adipose tissue (SAT) from two cohorts: participants with subacute COVID-19 (28-89 days post-infection) compared to pre-pandemic controls, and participants with Long COVID compared to those with those classified as "indeterminate" based on the RECOVER-Adult Long COVID Research Index (12-47 months post-infection). We found no evidence of persistent SARS-CoV-2 RNA in adipose tissue in any participant. SAT from participants with subacute COVID-19 displayed significant transcriptional remodeling, including depleted immune activation pathways and upregulated Hox genes and integrin interactions, suggesting resident immune cell exhaustion and perturbations in tissue function. However, no consistent changes in gene expression were observed between Long COVID samples and samples from indeterminant participants. Thus, SAT may contribute to inflammatory dysregulation following COVID-19, but does not appear to play a clear role in Long COVID pathophysiology. Further research is needed to clarify the role of adipose tissue in COVID-19 recovery.

DOI: https://doi.org/10.1101/2025.05.23.655815