bims-musmir 2025-02-23 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–02–23
thirteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

CRISPR/Cas9-Targeted Myostatin Deletion Improves the Myogenic Differentiation Parameters for Muscle-Derived Stem Cells in Mice.
Peripheral defects precede neuromuscular pathology in the Smn2B/- mouse model of spinal muscular atrophy.
Re-Analyses of Samples From Amyotrophic Lateral Sclerosis Patients and Controls Identify Many Novel Small RNAs With Diagnostic And Prognostic Potential.
GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
A primer on global molecular responses to exercise in skeletal muscle: Omics in focus.
Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients.
Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.
Effect and mechanism of miRNA-144-5p-regulated autophagy in older adults with Sarcopenia.
miR-196-5p regulates myogenesis and induces slow-switch fibers formation by targeting PBX1.
ArfGAP3 Protects Mitochondrial Function and Promotes Autophagy Through Rab5a-Mediated Signals in Ageing Skeletal Muscle.
Competition effects regulating the composition of the microRNA pool.
Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
Cachexia Alters Central Nervous System Morphology and Functionality in Cancer Patients.

J Dev Biol. 2025 Feb 11. pii: 5. [Epub ahead of print]13(1):

CRISPR/Cas9-Targeted Myostatin Deletion Improves the Myogenic Differentiation Parameters for Muscle-Derived Stem Cells in Mice.

Mohamed I Elashry, Victoria C Schneider, Manuela Heimann, Sabine Wenisch, Stefan Arnhold.

  Skeletal muscle plays a pivotal role in physical activity, protein storage and energy utilization. Skeletal muscle wasting due to immobilization, aging, muscular dystrophy and cancer cachexia has negative impacts on the quality of life. The deletion of myostatin, a growth and differentiation factor-8 (GDF-8) augments muscle mass through hyperplasia and hypertrophy of muscle fibers. The present study examines the impact of myostatin deletion using CRISPR/Cas9 editing on the myogenic differentiation (MD) of C2C12 muscle stem cells. A total of five myostatin loci were targeted using guided RNAs that had been previously cloned into a vector. The clones were transfected in C2C12 cells via electroporation. The cell viability and MD of myostatin-edited clones (Mstn-/-) were compared with C2C12 (Mstn+/+) using a series of assays, including MTT, sulforhodamine B, immunocytochemistry, morphometric analysis and RT-qPCR. The clones sequenced showed evidence of nucleotides deletion in Mstn-/- cells. Mstn-/- cells demonstrated a normal physiological performance and lack of cytotoxicity. Myostatin depletion promoted the myogenic commitment as evidenced by upregulated MyoD and myogenin expression. The number of MyoD-positive cells was increased in the differentiated Mstn-/- clones. The Mstn-/- editing upregulates both mTOR and MyH expression, as well as increasing the size of myotubes. The differentiation of Mstn-/- cells upregulates ActRIIb; in contrast, it downregulates decorin expression. The data provide evidence of successful CRISPR/Cas9-mediated myostatin deletion. In addition, targeting myostatin could be a beneficial therapeutic strategy to promote MD and to restore muscle loss. In conclusion, the data suggest that myostatin editing using CRISPR/Cas9 could be a potential therapeutic manipulation to improve the regenerative capacity of muscle stem cells before in vivo application.

Keywords:  CRISPR/Cas9; muscle stem cells; myogenic differentiation; myostatin

DOI:  https://doi.org/10.3390/jdb13010005
J Neuromuscul Dis. 2024 Nov;11(6): 1200-1210

Peripheral defects precede neuromuscular pathology in the Smn2B/- mouse model of spinal muscular atrophy.

Aoife Reilly, Ariane Beauvais, Majd Al-Aarg, Rebecca Yaworski, Emma R Sutton, Simon Thebault, Rashmi Kothary.

   BACKGROUND: Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative disease caused by the loss or mutation of the survival motor neuron 1 (SMN1) gene. Though classically regarded as a motor neuron disorder, reports are increasingly describing the involvement of non-neuronal organs in SMA. The Smn2B/- mouse is a model of SMA that displays a peripheral phenotype including metabolic defects.
OBJECTIVE: Here, we characterized several neuronal and non-neuronal defects in the Smn2B/- mouse throughout development to better understand the progression of the disease and the relationship between tissue defects.
METHODS: We collected tissues from mutant Smn2B/- mice and Smn2B/+ littermate controls at several timepoints and evaluated spinal cord motor neuron loss, neuromuscular junction pathology, muscle fiber size, liver steatosis, and pancreatic islet cell composition. Blood glucose and plasma neurofilament light chain (NfL) were also measured.
RESULTS: Smn2B/- mice displayed several peripheral defects prior to motor neuron loss and showed early elevations in neurofilament light chain (NfL) protein.
CONCLUSIONS: This work provides an important framework for guiding future research with this mouse model and demonstrates that the liver may be an early target in the development of SMA.

Keywords:  animal models; biomarkers; blood glucose; liver; metabolism; motor neurons; muscles; neurofilament protein; neuromuscular junction; pancreas

DOI:  https://doi.org/10.1177/22143602241288036
Mol Neurobiol. 2025 Feb 21.

Re-Analyses of Samples From Amyotrophic Lateral Sclerosis Patients and Controls Identify Many Novel Small RNAs With Diagnostic And Prognostic Potential.

Phillipe Loher, Eric Londin, Hristelina Ilieva, Piera Pasinelli, Isidore Rigoutsos.

  Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease for which accurate diagnostic and prognostic biomarkers are needed. Toward this goal, we reanalyzed two published collections of datasets generated from the plasma and serum of ALS patients and controls. We profiled these datasets for isoforms of microRNAs (miRNAs) known as isomiRs, transfer RNA-derived fragments (tRFs), and ribosomal RNA-derived fragments (rRFs), placing all remaining reads into a group labeled "not-itrs." We found that plasma and serum are rich in isomiRs (canonical, non-canonical, and non-templated), tRFs, rRFs, and members of an emerging class of small RNAs known as Y RNA-derived fragments (yRFs). In both analyzed collections, we found many isomiRs, tRFs, rRFs, and yRFs that are differentially abundant between patients and controls. We also performed a survival analysis that considered Riluzole treatment status, demographics (age at onset, age at enrollment, sex), and disease characteristics (ALSFRS, rD50, onset type) and found many of the differentially abundant small RNAs to be associated with survival time, with some of these associations being independent of Riluzole treatment. Unexpectedly, many not-itrs that did not map to the human genome mapped exactly to sequences from the SILVA database of ribosomal DNAs (rDNAs). Not-itrs from the plasma datasets mapped primarily to rDNAs from the order of Burkholderiales, and several of them were associated with patient survival. Not-itrs from the serum datasets also showed support for rDNA from Burkholderiales but a stronger support for rDNAs from the fungi group of the Nucletmycea taxon. The findings suggest that many previously unexplored small non-coding RNAs, including human isomiRs, tRFs, rRFs, and yRFs, could potentially serve as novel diagnostic and prognostic biomarkers for ALS.

Keywords:  ALS; Amyotrophic lateral sclerosis; Burkholderiales; Diagnostics; Nucletmycea; Prognostics; Y RNAs; isomiRs; miRNAs; rRFs; rRNAs; tRFs; tRNAs; yRFs

DOI:  https://doi.org/10.1007/s12035-025-04747-2
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13715

GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.

Stephen E Flaherty, LouJin Song, Bina Albuquerque, Anthony Rinaldi, Mary Piper, Dinesh Hirenallur Shanthappa, Xian Chen, John Stansfield, Shoh Asano, Evanthia Pashos, Trenton Thomas Ross, Srinath Jagarlapudi, Abdul Sheikh, Bei Zhang, Zhidan Wu.

   BACKGROUND: Primary mitochondrial myopathies (PMMs) are disorders caused by mutations in genes encoding mitochondrial proteins and proteins involved in mitochondrial function. PMMs are characterized by loss of muscle mass and strength as well as impaired exercise capacity. Growth/Differentiation Factor 15 (GDF15) was reported to be highly elevated in PMMs and cancer cachexia. Previous studies have shown that GDF15 neutralization is effective in improving skeletal muscle mass and function in cancer cachexia. It remains to be determined if the inhibition of GDF15 could be beneficial for PMMs. The purpose of the present study is to assess whether treatment with a GDF15 neutralizing antibody can alleviate muscle atrophy and physical performance impairment in a mouse model of PMM.
METHODS: The effects of GDF15 neutralization on PMM were assessed using PolgD257A/D257A (POLG) mice. These mice express a proofreading-deficient version of the mitochondrial DNA polymerase gamma, leading to an increased rate of mutations in mitochondrial DNA (mtDNA). These animals display increased circulating GDF15 levels, reduced muscle mass and function, exercise intolerance, and premature aging. Starting at 9 months of age, the mice were treated with an anti-GDF15 antibody (mAB2) once per week for 12 weeks. Body weight, food intake, body composition, and muscle mass were assessed. Muscle function and exercise capacity were evaluated using in vivo concentric max force stimulation assays, forced treadmill running and voluntary home-cage wheel running. Mechanistic investigations were performed via muscle histology, bulk transcriptomic analysis, RT-qPCR and western blotting.
RESULTS: Anti-GDF15 antibody treatment ameliorated the metabolic phenotypes of the POLG animals, improving body weight (+13% ± 8%, p < 0.0001), lean mass (+13% ± 15%, p < 0.001) and muscle mass (+35% ± 24%, p < 0.001). Additionally, the treatment improved skeletal muscle max force production (+35% ± 43%, p < 0.001) and exercise performance, including treadmill (+40% ± 29%, p < 0.05) and voluntary wheel running (+320% ± 19%, p < 0.05). Mechanistically, the beneficial effects of GDF15 neutralization are linked to the reversal of the transcriptional dysregulation in genes involved in autophagy and proteasome signalling. The treatment also appears to dampen glucocorticoid signalling by suppressing circulating corticosterone levels in the POLG animals.
CONCLUSIONS: Our findings highlight the potential of GDF15 neutralization with a monoclonal antibody as a therapeutic avenue to enhance physical performance and mitigate adverse clinical outcomes in patients with PMM.

Keywords:  GDF15; antibody; mice; mitochondria; muscle; primary mitochondrial myopathy

DOI:  https://doi.org/10.1002/jcsm.13715
J Sport Health Sci. 2025 Feb 15. pii: S2095-2546(25)00007-9. [Epub ahead of print] 101029

A primer on global molecular responses to exercise in skeletal muscle: Omics in focus.

Kevin A Murach, James R Bagley.

  Advances in skeletal muscle omics has expanded our understanding of exercise-induced adaptations at the molecular level. Over the past 2 decades, transcriptome studies in muscle have detailed acute and chronic responses to resistance, endurance, and concurrent exercise, focusing on variables such as training status, nutrition, age, sex, and metabolic health profile. Multi-omics approaches, such as the integration of transcriptomic and epigenetic data, along with emerging ribosomal RNA sequencing advancements, have further provided insights into how skeletal muscle adapts to exercise across the lifespan. Downstream of the transcriptome, proteomic and phosphoproteomic studies have identified novel regulators of exercise adaptations, while single-cell/nucleus and spatial sequencing technologies promise to evolve our understanding of cellular specialization and communication in and around skeletal muscle cells. This narrative review highlights (a) the historical foundations of exercise omics in skeletal muscle, (b) current research at 3 layers of the omics cascade (DNA, RNA, and protein), and (c) applications of single-cell omics and spatial sequencing technologies to study skeletal muscle adaptation to exercise. Further elaboration of muscle's global molecular footprint using multi-omics methods will help researchers and practitioners develop more effective and targeted approaches to improve skeletal muscle health as well as athletic performance.

Keywords:  Epigenomics; Phosphoproteomics; Proteomics; Single cell; Transcriptomics

DOI:  https://doi.org/10.1016/j.jshs.2025.101029
J Mol Neurosci. 2025 Feb 15. 75(1): 21

Metabolomic and Proteomic Profiling of Serum-Derived Extracellular Vesicles from Early-Stage Amyotrophic Lateral Sclerosis Patients.

Yara Al Ojaimi, Nicolas Vallet, Audrey Dangoumau, Débora Lanznaster, Clement Bruno, Antoine Lefevre, Samira Osman, Camille Dupuy, Patrick Emond, Patrick Vourc'h, Philippe Corcia, Zuzana Krupova, Charlotte Veyrat-Durebex, Hélène Blasco.

  The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage. Serum EVs were obtained from 9 healthy controls and 9 ALS patients. After EV purification, proteomic (LC‒MS/MS followed by TimsTOF Pro Mass Spectrometry) and metabolomic (Q Exactive mass spectrometer) analyses were performed. No differences in the size or concentration of EVs were observed between the controls and ALS patients. Proteomic analysis revealed 45 proteins differentially expressed in the EVs of ALS patients compared with those of controls. Metabolomic analysis revealed several distinctly represented metabolites involved in the citrate cycle and complex lipid metabolism between patients and controls. Interomics correlation analysis revealed 2 modules that were strongly associated with ALS and included several lipid metabolism-related proteins and metabolites. This study is the first to evaluate EVs by integrated proteomics and metabolomics in early-stage ALS patients, highlighting the technological progress in global inter-omics explorations of small biological samples. The differences observed in the levels of several exosomal proteins and metabolites, including phospholipids, could be used to identify serum biomarkers and novel players involved in ALS pathogenesis.

Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Extracellular vesicles; Omics

DOI:  https://doi.org/10.1007/s12031-025-02315-w
J Biomed Sci. 2025 Feb 18. 32(1): 29

Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.

Fasih A Rahman, Mackenzie Q Graham, Amanda M Adam, Emma S Juracic, A Russell Tupling, Joe Quadrilatero.

   BACKGROUND: Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.
METHODS: We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit autophagy.
RESULTS: Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.
CONCLUSION: These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.

Keywords:  Apoptosis; BNIP3; Disuse atrophy; Mitochondria; Mitophagy; Skeletal muscle

DOI:  https://doi.org/10.1186/s12929-025-01118-w
Immun Ageing. 2025 Feb 14. 22(1): 7

Effect and mechanism of miRNA-144-5p-regulated autophagy in older adults with Sarcopenia.

Mengdie Hu, Ying Zhang, Hong Ding, Rui Chao, Zhidong Cao.

   BACKGROUND: Advanced aging invariably triggers an overabundance of apoptosis, stemming from diminished autophagy or a disarray in cellular autophagic processes. This, in turn, leads to an accelerated breakdown of muscle proteins, which exacerbates the ongoing deterioration of skeletal muscle and intensifies the severity of senile sarcopenia. This study aimed to investigate the role and mechanism of miRNA-regulated autophagy in senile sarcopenia.
METHODS: The miRNAs associated with sarcopenia were screened, and the target genes of significant miRNAs were predicted. The effects of significantly differentially expressed miRNA-144-5p on cell aging and autophagy were validated in vivo and in vitro.
RESULTS: The inhibition of miR-144-5p enhanced the multiplication of mouse myoblasts, increased the expression of MHC and autophagic markers LC3II/LC3I and Beclin-1, facilitated the formation of autophagosomes in mouse myoblasts, and reduced the number of aging cells and the expression of senescence-related proteins acetylated p53, p53, and p21 expression in mouse myoblasts. miR-144-5p affects myoblast senescence, myogenic differentiation, and autophagy by regulating the downstream target gene, Atg2A. Inhibiting miR-144-5p markedly increased the grip strength of the posterior limb in old mice, and the CSA of old mice and young mice was also markedly increased.
CONCLUSION: All experiments have demonstrated that miRNA-144-5p has a significant impact on the regulation of autophagy and the development of senile sarcopenia.

Keywords:  Atg2A; Autophagy; Inflammation; Sarcopenia; miRNA-144-5p

DOI:  https://doi.org/10.1186/s12979-025-00499-8
Int J Biol Macromol. 2025 Feb 16. pii: S0141-8130(25)01686-1. [Epub ahead of print]305(Pt 1): 141137

miR-196-5p regulates myogenesis and induces slow-switch fibers formation by targeting PBX1.

Yufei Wang, Donghao Zhang, Songhang Yu, Weijie Zhang, Yuan Tang, Lingqian Yin, Zhongzhen Lin, Rui Zhou, Yupei Zhang, Lu Lu, Yiping Liu.

  Skeletal muscle, which is crucial for meat production, color, and quality is regulated by complex genetic mechanisms. MicroRNAs (miRNA), serve a crucial part in regulating skeletal muscle myogenesis together with the switching of muscle fiber types, but the identification of key miRNAs and their underlying molecular mechanism has been hindered. In the present study, miRNA sequencing was utilized to identify the differentially expressed miRNAs (DEMs) in different skeletal muscles, among which miR-196-5p was found notably upregulated in chicken soleus (SOL) muscles, suggesting the potential role of miR-196-5p in slow-switch fiber formation. Next, the gain- and loss-of-function experiments confirmed the inhibitory role and stimulatory effects of miR-196-5p on myoblast expansion, myotube maturation, and slow-switch myofibers formation, respectively. Through integrated bioinformatics and experimental analysis, the interaction between miR-196-5p and PBX1 was additionally clarified. PBX1 exhibits a promotive role in skeletal muscle myogenesis, while it exerts an inhibitory effect during the formation of slow-switch myofibers. In conclusion, we propose that miR-196-5p has an important involvement in modulating of skeletal muscle structural composition and function.

Keywords:  Myogenesis; PBX1; miR-196-5p

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.141137
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13725

ArfGAP3 Protects Mitochondrial Function and Promotes Autophagy Through Rab5a-Mediated Signals in Ageing Skeletal Muscle.

Mao Chen, Xiaoyu Huang, Bingshu Li, Ya Xiao, Liying Chen, Fangyi Zhu, Shasha Hong, Jianming Tang, Suting Li, Jie Min, Wenyi Jin, Yubiao Zhang, Lian Yang, Yang Li, Shufei Zhang, Li Hong.

   BACKGROUND: Few researches have investigated the molecular mechanism responsible for the age-related loss of the pelvic floor muscle (PFM) mass and functionality-a pivotal contributor to pelvic organ prolapse and diminished physical well-being. ADP ribosylation factor GTPase activating protein 3 (ArfGAP3) is a member of ArfGAPs, which regulates the vesicular trafficking pathway and intracellular proteins transporting. However, its effects on skeletal muscle ageing remain largely unknown.
METHODS: Mouse models of natural ageing and D-gal (D-galactose)-induced ageing were subject to analyse the structure, function and pathological alterations of the PFM and the expression of ArfGAP3. Stable ArfGAP3 knockdown and overexpression C2C12 cell lines were established to investigate the anti-senescence effects of ArfGAP3 and the underlying mechanisms in ageing process, complemented by Rab5a genetic intervention and mRFP-GFP-LC3 adenoviral particles transfection. In vivo experiments entailed ArfGAP3 overexpression in mice alongside autophagy inhibitor treatment, with assessments encompassing tissue mass, bladder leak point pressure (BLPP), submicroscopic structure, antioxidative stress system and muscle regeneration.
RESULTS: Aged (24-month-old) mice exhibited significant physiological alterations in PFMs, including decreased muscle mass, diminished cross-sectional area (CSA), deteriorated supporting function (as evidenced by reduced BLPP), impaired autophagy and increased levels of oxidative stress (p < 0.001). Utilizing ageing C2C12 model, we observed a dose-dependent relationship between D-gal induction and cellular senescence, impaired differentiation and mitochondrial damage. Remarkably, the expression levels of ArfGAP3 were markedly downregulated in both in vitro and in vivo ageing models. Knockdown of ArfGAP3 exacerbated impaired differentiation potential and induced aberrant mitochondrial morphology and functional dysfunction in ageing C2C12 myoblasts, whereas ArfGAP3 overexpression largely mitigated these effects. Mechanistically, our findings revealed an interplay between ArfGAP3 and Rab5a, indicating their coordinated regulation. ArfGAP3-mediated activation of Rab5a-associated autophagy and IRS1-AKT-mTOR signalling pathways during cellular senescence and myogenesis was identified, leading to enhanced autophagic flux and improved resistance to oxidative stress. In vivo, ArfGAP3 overexpression ameliorated D-gal-induced loss of muscle mass and function, while promoting antioxidant responses and muscle regeneration in mice. However, these protective effects of ArfGAP3 overexpression were extinguished by autophagy inhibition.
CONCLUSIONS: Our study uncovers the significant role of ArfGAP3 in enhancing differentiation capacity and mitochondrial function through mediating Rab5a expression to activate IRS1-AKT-mTOR signalling pathways and promote autophagy during the ageing process. These findings underscore the potential of ArfGAP3 as a promising therapeutic target for ameliorating the decline in skeletal muscle function associated with ageing.

Keywords:  ArfGAP3; Rab5a; ageing; autophagy; pelvic floor muscle

DOI:  https://doi.org/10.1002/jcsm.13725
J R Soc Interface. 2025 Feb;22(223): 20240870

Competition effects regulating the composition of the microRNA pool.

Sofia B Raak, Jonathan G Hanley, Cian O'Donnell.

  MicroRNAS (miRNAs) are short non-coding RNAs that can repress mRNA translation to regulate protein synthesis. During their maturation, multiple types of pre-miRNAs compete for a shared pool of the enzyme Dicer. It is unknown how this competition for a shared resource influences the relative expression of mature miRNAs. We study this process in a computational model of pre-miRNA maturation, fitted to in vitro Drosophila S2 cell data. We find that those pre-miRNAs that efficiently interact with Dicer outcompete other pre-miRNAs, when Dicer is scarce. To test our model predictions, we re-analysed previously published ex vivo mouse striatum data with reduced Dicer1 expression. We calculated a proxy measure for pre-miRNA affinity to TRBP (a protein that loads pre-miRNAs to Dicer). This measures well-predicted mature miRNA levels in the data, validating our assumptions. We used this as a basis to test the the model's predictions through further analysis of the data. We found that pre-miRNAs with strong TRBP association are over-represented in competition conditions, consistent with the modelling. Finally using further simulations, we discovered that pre-miRNAs with low maturation rates can affect the mature miRNA pool via competition among pre-miRNAs. Overall, this work presents evidence of pre-miRNA competition regulating the composition of mature miRNAs.

Keywords:  biosynthesis; competition; microRNAs

DOI:  https://doi.org/10.1098/rsif.2024.0870
bioRxiv. 2025 Jan 31. pii: 2025.01.28.635306. [Epub ahead of print]

Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.

Caroline Trumpff, Qiuhan Huang, Jeremy Michelson, Cynthia C Liu, David Shire, Christian G Habeck, Yaakov Stern, Martin Picard.

Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.

DOI: https://doi.org/10.1101/2025.01.28.635306
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13742

Cachexia Alters Central Nervous System Morphology and Functionality in Cancer Patients.

Estefania Simoes, Ricardo Uchida, Mariana P Nucci, Fabio L S Duran, Joanna D C C Lima, Leonardo R Gama, Naomi A Costa, Maria C G Otaduy, Fang C Bin, Jose P Otoch, Paulo Alcantara, Alexandre Ramos, Alessandro Laviano, Mauricio Berriel Diaz, Margaret M Esiri, Gabriele C DeLuca, Stephan Herzig, Geraldo Busatto Filho, Marilia Seelaender.

   BACKGROUND: Cachexia is a clinically challenging multifactorial and multi-organ syndrome, associated with poor outcome in cancer patients, and characterised by inflammation, wasting and loss of appetite. The syndrome leads to central nervous system (CNS) function dysregulation and to neuroinflammation; nevertheless, the mechanisms involved in human cachexia remain unclear.
METHODS: We used in vivo structural and functional magnetic resonance imaging (Cohort 1), as well as postmortem neuropathological analyses (Cohort 2) in cachectic cancer (CC) patients compared to weight stable cancer (WSC) patients. Cohort 1 included treatment-naïve adults diagnosed with colorectal cancer, further divided into WSC (n = 12; 6/6 [male/female], 61.3 ± 3.89 years) and CC (n = 10; 6/4, 63.0 ± 2.74 years). Cohort 2 was composed by human postmortem cases where gastrointestinal carcinoma was the underlying cause of death (WSC n = 6; 3/3, 82.7 ± 3.33 years and CC n = 10; 5/5, 84.2 ± 2.28 years).
RESULTS: Here we demonstrate that the CNS of CC patients presents regional structural differences within the grey matter (GM). Cachectic patients presented an augmented area within the region of the orbitofrontal cortex, olfactory tract and the gyrus rectus (coordinates X, Y, Z = 6, 20,-24; 311 voxels; pFWE = 0.023); increased caudate and putamen volume (-10, 20, -8; 110 voxel; pFWE = 0.005); and reduced GM in superior temporal gyrus and rolandic operculum (56,0,2; 156 voxels; pFWE = 0.010). Disrupted functional connectivity was found in several regions such as the salience network, subcortical and temporal cortical areas of cachectic patients (20 decreased and 5 increased regions connectivity pattern, pFDR < 0.05). Postmortem neuropathological analyses identified abnormal neuronal morphology and density, increased microglia/macrophage burden, astrocyte profile disruption and mTOR pathway related neuroinflammation (p < 0.05).
CONCLUSIONS: Our results indicate that cachexia compromises CNS morphology mostly causing changes in the GM of cachectic patients, leading to alterations in regional volume patterns, functional connectivity, neuronal morphology, neuroglia profile and inducing neuroinflammation, all of which may contribute to the loss of homeostasis control and to deficient information processing, as well as to the metabolic and behavioural derangements commonly observed in human cachexia. This first human mapping of CNS cachexia responses will now pave the way to mechanistically interrogate these pathways in terms of their therapeutic potential.

Keywords:  central nervous system; grey matter; human cachexia; neuroimaging; neuroinflammation; neuropathology

DOI:  https://doi.org/10.1002/jcsm.13742