bims-musmir 2025-09-14 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–09–14
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.
The Effect of Cachexia on the Feeding Regulation of Skeletal Muscle Protein Synthesis in Tumour-Bearing Mice.
Molecular subtypes of human skeletal muscle in cancer cachexia.
Defective mitochondrial quality control in the aging of skeletal muscle.
Amino Acid Metabolism in Cancer Cachexia and Chemotherapy Myotoxicity.
Valproic acid-based self-assembling nanoparticle prodrugs prevent skeletal muscle loss in cancer cachexia.
Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
Clinical, Immunological, and Vesicular Markers in Sarcopenia and Presarcopenia.
Molecular Pathogenesis of Sarcopenia: Regulatory Networks Involving MicroRNAs in Age-Related Skeletal Muscle Decline.
Treatment of mitochondrial disturbances due to early life adversity in mice results in restoration of complex I activity and normal reward behavior.
ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function.
Functional variants of CFAP410 affect the DNA damage response leading to motor neuron degeneration - Implications for ALS.
Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia.
O-GlcNAcase Inhibitor Improves Denervation-Induced Muscle Atrophy in Mice.
Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.

Am J Physiol Cell Physiol. 2025 Sep 10.

Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.

Thomas D Cardaci, Arianna V Bastian, Kasie Roark, Brooke M Bullard, Mitchell M NeSmith, Christian A Unger, Robert L Price, Jason L Kubinak, E Angela Murphy, Brandon N VanderVeen.

  Cachexia, the loss of skeletal muscle mass and function with cancer, contributes to reduced life quality and worsened survival. Skeletal muscle fibrosis leads to disproportionate muscle weakness; however, the role of infiltrating immune cells and fibro-adipogenic progenitors (FAPs) in cancer-induced muscle fibrosis is not well understood. Using the C26 model of cancer cachexia, we sought to examine the changes to skeletal muscle immune cells and FAPs which contribute to excessive extracellular matrix (ECM) collagen deposition. CD2F1 male mice (n=35) were implanted with either 106 C26 or CT-26 (weight stable; WS) cells. Skeletal muscle immune cell populations, satellite cells, and FAPs were examined using high-dimensional flow cytometry. Skeletal muscle ECM ultrastructure was assessed via scanning electron microscopy (SEM) of decellularized muscle along with transmission electron microscopy (TEM). Cachectic mice had significant decreases in body weight (-13.4%, p=0.003) and skeletal muscle mass (-37%, p=0.006). Cachectic mice had elevated CD45+CD11b+Ly6g+ neutrophils compared to non-tumor bearing controls (128%, p=0.016) and elevated CD45+CD11b+Ly6g-F480+CD206+MHCII- profibrotic macrophages and increased CD45-Sca1+CD106+CD140a+ FAPs compared to WS (43%, p=0.014) and controls (59%, p=0.002) with thickening of the ECM, particularly of the endomysium and perimysium. SEM and TEM analysis also identified clusters of infiltrating cells localized to regions of excessive ECM deposition in cachectic mice that were absent in WS and controls. These data highlight changes to the muscle microenvironment which contribute to fibrosis and excessive ECM deposition in cancer cachexia. Targeting pro-fibrotic immune cells may represent a promising therapeutic approach to mitigate muscle wasting and dysfunction with cachexia.

Keywords:  FAPs; atrophy; macrophages; muscle wasting; weakness

DOI:  https://doi.org/10.1152/ajpcell.00448.2025
J Cachexia Sarcopenia Muscle. 2025 ;16(5): e70064

The Effect of Cachexia on the Feeding Regulation of Skeletal Muscle Protein Synthesis in Tumour-Bearing Mice.

Brittany R Counts, Quan Zhang, Jessica L Halle, Melissa J Puppa, Stephen E Alway, Junaith Mohamed, Jeremy P Loenneke, James A Carson.

   BACKGROUND: Cancer promotes muscle wasting through an imbalance in the tightly regulated protein synthesis and degradation processes. An array of intracellular signalling pathways, including mTORC1 and AMPK, regulate protein synthesis, and these pathways are responsive to the muscle's microenvironment and systemic stimuli. Although feeding and fasting are established systemic regulators of muscle mTORC1 and protein synthesis, the cancer environment's impact on these responses during cachexia development is poorly understood. Although the IL-6 cytokine family has been widely investigated as a driver of cachexia with several cancers, how this signalling regulates muscle responses to feeding and fasting requires further study. We investigated if the cancer environment alters the feeding and fasting regulation of skeletal muscle protein synthesis and if the IL-6 family of cytokines signalling through muscle glycoprotein 130 could regulate this response.
METHODS: Male C57BL/6J mice were subcutaneously injected with 1 × 106 LLC cells or PBS. Mice were euthanized 25-30 days post-injection after a 12-h dark cycle fast, followed by access to food pellets for 1 h (fed) or immediately sacrificed. To determine AMPK and gp13's regulation of protein synthesis and anabolic signalling, we injected tamoxifen-inducible skeletal muscle AMPKa1a2 or gp130 knockout and floxed control mice with LLC cells or PBS. The gastrocnemius muscle was analysed for protein expression.
RESULTS: Feeding increased p-rpS6 and protein synthesis in PBS (2.2- and 0.4-fold, p < 0.001) and LLC mice (1.7- and 0.9-fold, p < 0.001), but overall, LLC significantly reduced p-rpS6 and protein synthesis. Feeding only increased p-AKT in PBS mice (1.5-fold, p < 0.001). In vitro LLC-conditioned media did not inhibit the insulin induction of myotube p-AKT (p < 0.001) and p-rpS6 (p < 0.001). Muscle gp130 loss reduced the fasting p-AMPK induction in LLC mice but did not alter suppression of p-AKT and p-rpS6 and protein synthesis. Muscle AMPK loss increased p-rpS6 (2.1-fold, p < 0.001) and protein synthesis (0.7-fold, p < 0.001) in PBS mice but did not restore LLC-suppressed protein synthesis.
CONCLUSIONS: Our study provides novel insight into muscle responsiveness to feeding and fasting in a cancer environment. We find the acute anabolic response to feeding is maintained during LLC-induced cachexia, whereas the fasting catabolic response is exacerbated. Muscle-specific gp130 loss prevented disrupted fasting AMPK activation but not protein synthesis. There is a need to understand the aberrant upstream and downstream regulation of muscle AMPK activity that is disrupted with cancer and leads to aberrant protein turnover regulation.

Keywords:  anabolism; cancer; fasting; feeding; inflammation

DOI:  https://doi.org/10.1002/jcsm.70064
Nature. 2025 Sep 10.

Molecular subtypes of human skeletal muscle in cancer cachexia.

Bhumi J Bhatt, Sunita Ghosh, Vera Mazurak, Aurélien Q Brun, Oliver Bathe, Vickie E Baracos, Sambasivarao Damaraju.

Cancer-associated muscle wasting is associated with poor clinical outcomes1, but its underlying biology is largely uncharted in humans2. Unbiased analysis of the RNAome (coding and non-coding RNAs) with unsupervised clustering using integrative non-negative matrix factorization3 provides a means of identifying distinct molecular subtypes and was applied here to muscle of patients with colorectal or pancreatic cancer. Rectus abdominis biopsies from 84 patients were profiled using high-throughput next-generation sequencing. Integrative non-negative matrix factorization with stringent quality metrics for clustering identified two highly coherent molecular subtypes within muscle of patients with cancer. Patients with subtype 1 (versus subtype 2) showed clinical manifestations of cachexia: high-grade weight loss, low muscle mass, atrophy of type IIA and type IIX muscle fibres, and reduced survival. On the basis of differential expression between the subtypes, we identified biological processes that may contribute to cancer-associated loss of muscle mass and function, including altered posttranscriptional regulation and perturbation of neuronal systems; cytokine storm and cellular immune response; pathways related to extracellular matrix; and metabolic abnormalities spanning xenobiotic metabolism, haemostasis, signal transduction, embryonic and/or pluripotent stem cells, and amino acid metabolism. Differential expression between subtypes indicated the involvement of multiple intertwined higher-order gene regulatory networks, suggesting that network interactions of (hub) long non-coding RNAs, microRNAs and mRNAs could represent targets for future research.

DOI: https://doi.org/10.1038/s41586-025-09502-0
Mech Ageing Dev. 2025 Sep 08. pii: S0047-6374(25)00088-0. [Epub ahead of print]228 112112

Defective mitochondrial quality control in the aging of skeletal muscle.

Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Francesco Landi, Anna Picca.

  Age-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation-contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span.

Keywords:  Autophagy; Damage associated molecular patterns; Mitochondrial DNA; Mitochondrial dynamics; Mitophagy; Myocyte; Proteasome

DOI:  https://doi.org/10.1016/j.mad.2025.112112
Am J Physiol Cell Physiol. 2025 Sep 10.

Amino Acid Metabolism in Cancer Cachexia and Chemotherapy Myotoxicity.

Meghan V McCue, David A MacLean.

  Cancer induced skeletal muscle wasting (cachexia) is responsible for over 20% of cancer related deaths, yet much about the pathophysiology of the condition remains unknown. Importantly, cancer cachexia does not seem wholly responsive to traditional anabolic stimuli such as nutritional interventions. It is possible that tumours directly or indirectly target skeletal muscle for their dynamic and abundant pool of amino acids that can be reliably used by tumours to supplement energy production and biomass synthesis. Therefore, understanding how the presence of a tumour alters circulating and tissue level amino acid pools could provide valuable insight into tumour induced muscle wasting. The purpose of this review was to examine the current body of research that has studied amino acids in the context of cancer cachexia, to better understand how amino acids behave during the development of cancer, cachexia, and various cancer chemotherapies. Distinct heterogeneity was observed in the behaviour of amino acids when comparing weight stable vs. cachectic patients with cancer, and there may be important temporal considerations based on rhythmic changes in amino acid turnover and mealtimes. Overall, there was very little consistency in the reported fluctuations of amino acids from study to study, suggesting there may be heterogenous pathophysiology based on tumour type, stage, and patient age and co-morbidities. Further work is required to characterize longitudinal changes in amino acid metabolism with consideration for these factors. Enhancing our understanding of amino acid metabolism during cancer cachexia could provide opportunities for advancement in practical methodologies in cachexia research and treatment strategies.

Keywords:  Amino Acid; Cachexia; Cancer; Muscle wasting; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00085.2025
Colloids Surf B Biointerfaces. 2025 Sep 05. pii: S0927-7765(25)00627-7. [Epub ahead of print]257 115120

Valproic acid-based self-assembling nanoparticle prodrugs prevent skeletal muscle loss in cancer cachexia.

Shoki Kamemaru, Yutaka Ikeda, Yukio Nagasaki.

  Cancer cachexia is a multifactorial syndrome characterized by persistent skeletal muscle loss, affecting 80 % of patients with advanced cancer and accounting for 20 % of cancer-related deaths. Despite its prevalence, effective treatment options remain limited due to the side effects and poor pharmacokinetic (PK) profiles of existing therapeutics, including valproic acid (VPA). To overcome these limitations, we developed self-assembling VPA-based nanoparticle prodrugs (abbreviated as NanoVPA), consisting of amphiphilic block copolymers, in which VPA is covalently conjugated via ester linkages. NanoVPA significantly improved the PK profile of VPA by suppressing initial rapid plasma concentration spikes and achieving sustained VPA release, maintaining circulation for up to 48 h and enhancing skeletal muscle accumulation within 10 h post-administration. In vivo, twice-weekly administration of NanoVPA significantly attenuated skeletal muscle loss in a cancer cachexia model by downregulating the expression of atrogin-1, a key muscle-specific ubiquitin ligase involved in proteolysis. These findings highlight the potential of NanoVPA as a novel therapeutic strategy for cancer cachexia, offering improved efficacy and reduced dosing frequency with minimized side effects.

Keywords:  Atrogin-1; Cancer cachexia; Polymeric micelles; Self-assembling nanoparticle prodrugs; Sustained drug release; Valproic acid (VPA)

DOI:  https://doi.org/10.1016/j.colsurfb.2025.115120
Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI:  https://doi.org/10.1080/15548627.2025.2561073
Front Biosci (Landmark Ed). 2025 Aug 27. 30(8): 42063

Clinical, Immunological, and Vesicular Markers in Sarcopenia and Presarcopenia.

Liudmila M Shuliko, Dmitry A Svarovsky, Liudmila V Spirina, Ikponmwosa Jude Ogieuhi, Olga E Akbasheva, Mariia V Matveeva, Iuliia G Samoilova, Valeria A Shokalo, Sofia S Timoshenko, Sofia M Merkulova, Amin I Ragimov, Mar'yam P Shukyurova, Natalia V Tarasenko.

   BACKGROUND: Sarcopenia is a complex, multifactorial condition characterized by progressive loss of muscle mass, strength, and function. Despite growing awareness, the early diagnosis and pathophysiological characterization of this condition remain challenging due to the lack of integrative biomarkers.
OBJECTIVE: This study aimed to conduct a comprehensive multilevel profiling of clinical parameters, immune cell phenotypes, extracellular vesicle (EV) signatures, and biochemical markers to elucidate biological gradients associated with different stages of sarcopenia.
MATERIALS AND METHODS: A prospective cohort study enrolled adults aged 45-85 years classified as control, presarcopenic, or sarcopenic based on European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. Clinical evaluation included anthropometry, muscle strength, sarcopenia screening (SARC-F) questionnaire/Short Physical Performance Battery (SPPB) questionnaires, and quality-of-life assessment. Flow cytometry was used to characterize blood monocyte/macrophage subsets (cluster of differentiation 14 (CD14), CD68, CD163, CD206). EVs were isolated from plasma and profiled for surface tetraspanins and matrix metalloproteinases (MMP2, MMP9, tissue inhibitor of metalloproteinase-1 (TIMP-1)) using bead-based flow cytometry. Biochemical assays measured metabolic, inflammatory, and extracellular matrix (ECM)-related markers. Data were analyzed via Kruskal-Wallis testing, discriminant analysis, and principal component analysis (PCA).
RESULTS: Sarcopenia, a muscle-wasting condition linked to aging, is characterized by chronic inflammation, proteolytic imbalance, and metabolic disturbances. Clinical deterioration is evident through reduced appendicular lean mass (ALM), appendicular skeletal muscle index (ASMI), SPPB scores, and sarcopenia quality of life (SarQoL) domains. Principal component analysis (PCA) identified four functional marker clusters: ECM degradation (MMP-positive EVs), inflammatory and homeostasis-stabilizing macrophages, and metabolic disruption (glucose, asprosin, triglycerides). Discriminant analysis emphasized vesicular and immune markers with significant classification potential, even when univariate differences were non-significant. Metabolic destabilization and inflammatory activation are detectable in presarcopenia stages. Chronic inflammation, characterized by CD14-CD163+206+ cells releasing pro-inflammatory cytokines, accelerates muscle degradation. Proteolytic dysfunction, with an imbalance between proteases and inhibitors, further contributes to muscle loss. Metabolic disorders impair energy production and nutrient utilization, exacerbating muscle wasting. A comprehensive assessment, including anthropometric, functional, physical activity, and QoL measures, is crucial for identifying high-risk individuals and understanding sarcopenia's mechanisms. Vesicular biomarkers, regulating tissue remodeling and inflammation, provide valuable insights. Standardized assessment methods are essential for enhancing diagnostic accuracy and intervention effectiveness. Future research should focus on developing and refining biomarkers to improve specificity and sensitivity, enabling targeted therapies and better QoL.
CONCLUSIONS: Integrating clinical, immunological, and biochemical markers with EVs helps stratify sarcopenia effectively. Our data shows that EVs and macrophage profiles reflect systemic changes and metabolic stress. However, age- and gender-related variability in our cohort warrants caution in generalizing the findings. Artificial intelligence (AI) enhances patient clustering by combining these data types, enabling precise, personalized sarcopenia management, predicting disease progression, and identifying high-risk patients. AI also standardizes and optimizes analytical protocols, improving diagnostic and monitoring reliability and reproducibility.

Keywords:  asprosin; extracellular vesicles; macrophages; matrix metalloproteinases; meteorin-like protein; monocytes; proteases; sarcopenia; vitronectin; α1-antitrypsin

DOI:  https://doi.org/10.31083/FBL42063
Front Biosci (Landmark Ed). 2025 Aug 29. 30(8): 38106

Molecular Pathogenesis of Sarcopenia: Regulatory Networks Involving MicroRNAs in Age-Related Skeletal Muscle Decline.

Joseph Joju Kalan, Lijo N Varghese, Rajesh Katare.

  Sarcopenia is the progressive loss of skeletal muscle mass, strength, and function, significantly contributing to frailty, disability, and mortality in aging populations. As life expectancy rises, sarcopenia presents a growing public health challenge, increasing healthcare costs, and diminishing quality of life. Despite its prevalence, sarcopenia is often underdiagnosed due to limitations in current diagnostic tools, including the lack of standardized cut-off values and reliance on physical performance tests. The causes of sarcopenia are multifactorial, involving oxidative stress, chronic inflammation, mitochondrial dysfunction, satellite cell depletion, and impaired angiogenesis. Recent research highlights the role of microRNAs (miRs) in regulating these molecular pathways. miRs influence muscle homeostasis by modulating gene expression related to muscle atrophy, apoptosis, inflammation, and insulin resistance. While non-pharmacological interventions such as resistance training and blood flow restriction therapy remain the primary treatment strategies, their effectiveness is often limited in older adults with reduced muscle regenerative capacity. The identification of miRs as biomarkers could enhance early diagnosis and enable more personalized treatment approaches. However, further research is required to validate their clinical utility and therapeutic potential. This review comprehensively analyses the molecular mechanisms underlying sarcopenia, current diagnostic challenges, and emerging miR-based strategies that could transform its management. Future efforts should focus on integrating these molecular insights into clinical practice to improve early detection and intervention strategies.

Keywords:  aging; microRNAs; molecular mechanisms; muscle; sarcopenia; skeletal

DOI:  https://doi.org/10.31083/FBL38106
eNeuro. 2025 Sep 11. pii: ENEURO.0172-25.2025. [Epub ahead of print]

Treatment of mitochondrial disturbances due to early life adversity in mice results in restoration of complex I activity and normal reward behavior.

Kathie L Eagleson, Pat Levitt.

The environment experienced by children, such as exposure to chronic early life adversity (ELA), increases lifespan brain disorder risk. The mechanisms that link ELA exposure to functional brain disruptions are not well understood. A limited-bedding and nesting paradigm, in which ELA is induced in mouse pups over the first postnatal week through disruption of maternal care, is characterized by limited resources, environment unpredictability, and disruption of reward and cognitive behaviors. Studies using this model demonstrated sex-selective alterations in hippocampal mitochondrial-associated proteins in response to ELA compared to care as usual (CAU). Further, oxidative phosphorylation (OXPHOS) capacity and complex I activity are increased in ELA juveniles, yet decreased in adults, with the impact of ELA moderated by sex in female adults. Given that altered mitochondrial function is a key mediator in metabolic adaptations, the goal of the present study was to evaluate the possibility of reversing mitochondrial dysfunction and the anhedonia that accompanies ELA by addressing oxidative stress. Treatment with the antioxidant MitoQ began at weaning and extended to 3 months. Measures of complex I activity demonstrated full recovery in adults. Female-specific deficits in the sucrose preference task, which is a measure of rewarding behavior in rodents, also exhibited recovery, with preference for sucrose comparable to that of CAU mice. These data indicate that mitochondrial health is one component of responses to early life adversity that has lifespan implications, but with the capacity to recover normal functioning in adults.Significance Statement Chronic early life stress in humans and animals leads to enduring functional changes to brain circuitry and behavior. An emerging concept involves the adaptation of mitochondria to address new energy demands as a primary cellular response to chronic stress. Long-term disruptions lead to oxidative stress, anhedonia and cognitive deficits. To determine if direct treatment of oxidative stress can mitigate adult dysfunction, an 8-week regimen of an antioxidant was administered to post-weaning mice that were raised early postnatally in an environment that disrupts predictable maternal care. Complex I mitochondrial energetics and sucrose preference were restored to levels comparable to mice raised in care as usual conditions, demonstrating a link between mitochondrial health and functional outcomes.

DOI: https://doi.org/10.1523/ENEURO.0172-25.2025
FEBS Lett. 2025 Sep 12.

ACSS2 involved in acetyl-CoA synthesis regulates skeletal muscle function.

Mekala Gunasekaran, Gloriana Campos, Natalya M Wells, Khanhlinh Lambuu, Isabelle Draper, Christina A Pacak, Peter B Kang.

  Acyl-coenzyme A synthetase short-chain family member-2 (ACSS2) catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the discovery of a muscular dystrophy associated with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a key enzyme in cholesterol synthesis, we studied Acss2 in mice and the orthologous gene AcCoA in flies. Skeletal muscle from Acss2-/- mice showed atrophic fibers, lipid accumulation, and depleted NADH levels, while myoblasts from these mice displayed precocious differentiation. Exercise induced fatigue in the Acss2-/- mice, which was accentuated by inhibition of ATP-citrate lyase (ACLY) activity. AcCoA knockdown yielded reduced body sizes and locomotor defects in Drosophila. ACSS2 is vital for skeletal muscle function and merits study as a potential factor in muscle diseases related to cholesterol metabolism. Impact statement ACSS2 catalyzes the conversion of acetate to acetyl-CoA, regulating cholesterol metabolism. Given the increasingly apparent links between cholesterol metabolism and skeletal muscle function, we investigated ACSS2 deficiency in mouse and fly models. We identified defects in muscle morphology, muscle metabolism, and motor function. ACSS2 is vital for skeletal muscle.

Keywords:  ACSS2; cholesterol metabolism; muscle development

DOI:  https://doi.org/10.1002/1873-3468.70152
iScience. 2025 Sep 19. 28(9): 113338

Functional variants of CFAP410 affect the DNA damage response leading to motor neuron degeneration - Implications for ALS.

Ross Ferguson, Vasanta Subramanian.

  Mutations in CFAP410, a basal body protein known to be required for the formation of primary cilia, have been identified as risk modifiers in amyotrophic lateral sclerosis (ALS), a devastating late onset neurodegenerative disorder with poor prognosis. CFAP410 is also implicated in the DNA damage response and interacts with Nek1, which has been shown to be mutated in ALS. Herein, we investigated the effect of knocking in an HA epitope tag and functional mutations into the endogenous Cfap410 gene by gene editing in mouse embryonic stem cells (mESCs). We show that primary cilia in these edited mESCs, as well as in the neural progenitors and neurons differentiated from them do not exhibit any significant difference in frequency. However, ESCs, neural progenitors, and neurons with knock-in Cfap410 variants are more susceptible to DNA damage and exhibit impaired interaction with Nek1. Our findings point to DNA damage as a convergent pathway leading to ALS.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.113338
Nat Aging. 2025 Sep 10.

Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia.

Mengyan Hu, Xinmei Kang, Zhiruo Liu, Shisi Wang, Sanxin Liu, Chunyi Li, Danli Lu, Qin Qin, Yuxin Liu, Haotong Yi, Liling Yuan, Quentin Liu, Zhengqi Lu, Wei Cai.

Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment with Tspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy.

DOI: https://doi.org/10.1038/s43587-025-00956-5
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70066

O-GlcNAcase Inhibitor Improves Denervation-Induced Muscle Atrophy in Mice.

Tomoyasu Suenaga, Shouji Matsushima, Tomoka Masunaga, Toru Hashimoto, Shingo Takada, Yoshizuki Fumoto, Soichiro Hata, Kohtaro Abe, Shintaro Kinugawa.

   BACKGROUND: Skeletal muscle atrophy occurs in various situations, such as denervation, fasting and ageing. Disruption of the balance between protein synthesis and degradation plays an important role in muscle atrophy, and impaired Akt phosphorylation is considered to be crucial in this process. The attachment of an O-linked N-acetylglucosamine motif (O-GlcNAcylation), which is a post-translational modification mediated by the hexosamine biosynthetic pathway, an alternative pathway of glycolysis, is involved in the regulation of protein function. Akt O-GlcNAcylation interacts with Akt phosphorylation, thereby regulating its function. The purpose of this study was to clarify the role of O-GlcNAcylation in skeletal muscle atrophy and to identify a therapeutic target for its prevention.
METHODS: Denervation was induced by cutting the sciatic nerve on the right leg of male C57BL/6J mice. A sham operation was performed on the left leg. Three days after the operation, the mice were divided into two groups: One group was treated with the O-GlcNAcase inhibitor thiamet G (1 mg/kg body weight/day), and the other group was treated with vehicle. Seven days after the operation, the gastrocnemius muscle was collected and analysed. The effect of adeno-associated virus serotype 1-mediated suppression of O-GlcNAcase on skeletal muscle atrophy was also investigated. Finally, in C2C12 myotubes with adenovirus-mediated overexpression of wild-type Akt and O-GlcNAcylation-resistant mutant Akt (T479A), the interaction between the phosphorylation and O-GlcNAcylation of Akt was investigated.
RESULTS: The weight of denervated gastrocnemius muscle was decreased by 35.6% (p < 0.05) compared with sham. Akt phosphorylation was decreased by 27.8% (p < 0.05), and the expression of the muscle-specific ubiquitin ligases muscle atrophy F-box (atrogin-1) and muscle RING Finger-1 (MuRF1) was increased in denervated muscle compared with sham. Akt O-GlcNAcylation was decreased in denervated muscle compared with sham by 45.3% (p < 0.05), together with an 8.9-fold increase in O-GlcNAcase expression. Thiamet G reduced gastrocnemius muscle weight loss by 22.7% (p < 0.05) compared with vehicle, and this was achieved through an increase in Akt phosphorylation by 63.5% (p < 0.05) and decreases in atrogin-1 and MuRF1 expression. The inhibition of O-GlcNAcase by gene silencing also improved skeletal muscle atrophy. The overexpression of mutant Akt (T479A) showed less O-GlcNAcase inhibition-induced Akt phosphorylation than the overexpression of wild-type Akt.
CONCLUSIONS: O-GlcNAcase inhibition improved denervation-induced skeletal muscle atrophy in mice by increasing Akt O-GlcNAcylation. O-GlcNAcase may hence be a therapeutic target for preventing skeletal muscle atrophy.

Keywords:  O‐GlcNAcase; O‐GlcNAcylation; denervation‐induced muscle atrophy; phosphorylation; skeletal muscle; thiamet G

DOI:  https://doi.org/10.1002/jcsm.70066
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Sep 09. pii: S0278-5846(25)00245-3. [Epub ahead of print] 111491

Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.

Authors Jana Hroudová, Zdeněk Fišar.

  Alterations in mitochondrial energy metabolism, impaired processes of mitochondrial dynamics and mitophagy have recently been identified as important contributors to the pathophysiology of Alzheimer's disease (AD). Genetic predispositions and defects in mitochondrial metabolism, particularly within the electron transport chain of the oxidative phosphorylation system, have been linked to the pathology of intracellular and extracellular amyloid-beta (Aβ) and tau protein. This review summarizes the current molecular background of AD and explains the relationships between genetic factors, impaired energy metabolism, and the formation of pathological proteins. It highlights altered mitochondrial dynamics, impaired mitochondrial signaling, mitophagy, neuroinflammation, and apoptosis. Based on these findings, the review discusses mitochondrial biomarkers and novel molecules targeting mitochondrial dysfunction in the pathophysiology of AD.

Keywords:  Alzheimer's disease; Amyloid beta; Energy metabolism; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111491