bims-musmir 2026-04-19 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–04–19
seventeen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Unacylated Ghrelin Counteracts Mitochondrial Dysfunction and Neuromuscular Junction Disruption in Cancer Cachexia.
Cancer cachexia: A tumor-driven disorder of whole-body homeostasis.
Overactive PDGFRα and PDGFRβ promote distinct phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving muscle growth.
Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.
Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.
Oleuropein-based olive leaf extract enhances muscle mitochondrial bioenergetics response to moderate - but not maximal - intensity exercise in humans.
BCL6 regulates skeletal muscle mass and mitochondrial bioenergetics.
Single-Nucleus RNA Sequencing Reveals Muscle Fiber Cell Heterogeneity During Human Skeletal Muscle Aging.
Muscle mass, function and performance across the adult lifespan: the study of muscle, mobility and ageing.
Multitissue, multi-time point transcriptomic atlas of aging in mice and rats.
Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans.
Pathogenesis, Diagnostic Pathways, and New Therapeutic and Nutritional Strategies for Pancreatic Cancer-Associated Cachexia.
Up-regulation of miR-548 m Leading to Neuroinflammation to Promote the Progression of Alzheimer's Disease.
Development of a spatially defined 3D in vitro coculture construct modelling pancreatic cancer-associated cachexia.
Sarcopenic obesity and sarcopenia in relation to frailty, independent of locomotive syndrome: the DETECt-L cross-sectional study.
Whole-organism spatial transcriptomics at single-cell resolution in C. elegans.
Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle.

Am J Physiol Cell Physiol. 2026 Apr 14.

Unacylated Ghrelin Counteracts Mitochondrial Dysfunction and Neuromuscular Junction Disruption in Cancer Cachexia.

Bumsoo Ahn, Jonathan Wanagat, Caroline Cleary, Hannah C Ainsworth, Hyunyoung Kim.

  Cancer cachexia is a multifactorial metabolic syndrome that profoundly reduces muscle mass, strength, efficacy of chemotherapy, and survival, yet no effective therapy exists. Unacylated ghrelin (UnAG), the predominant form of circulating ghrelin, promotes muscle growth and mitochondrial bioenergetics, but its role in cancer cachexia remains unknown. Four- to five-month-old male C57Bl/6N mice were assigned to three groups: non-tumor-bearing (NTB), tumor-bearing (TB), and tumor-bearing treated with UnAG (TB+UnAG). Lewis Lung Carcinoma cells were inoculated subcutaneously in the flank of the mice. Body weight, food intake, and tumor size were monitored for four weeks. Lower limb muscle mass, contractile function, mitochondrial respiration, and reactive oxygen species (ROS) production were measured, in conjunction with western blot, proteomic, and immunohistochemical analyses. Compared with NTB controls, TB mice exhibited marked loss of muscle mass and function, whereas UnAG treatment preserved ~50% of the muscle mass and ~70% of the contractile force. UnAG enhanced mitochondrial oxygen consumption, reduced ROS generation, and preserved mitochondrial DNA copy number and downregulated DNA mutation frequency. TB mice demonstrated increased oxidative stress and activation of protein degradation pathways, along with neuromuscular junction disruption-both of which were normalized by UnAG. These findings collectively demonstrate that UnAG mitigates cancer cachexia by modulating mitochondrial bioenergetics, oxidative and proteolytic stress, and neuromuscular junction integrity. UnAG represents a promising therapeutic candidate that may mitigate cachexia and improve both chemotherapy efficacy and the quality of life of cancer patients.

Keywords:  Cancer cachexia; contractile properties; mitochondria; mitochondrial DNA; muscle wasting; unacylated ghrelin

DOI:  https://doi.org/10.1152/ajpcell.00917.2025
Cancer Cell. 2026 Apr 16. pii: S1535-6108(26)00166-2. [Epub ahead of print]

Cancer cachexia: A tumor-driven disorder of whole-body homeostasis.

Yuqing Zhang, Ryan D Nipp, Tobias Janowitz, Yi-Ping Li, Denis C Guttridge, Min Li.

  Cancer cachexia is a systemic metabolic syndrome driven by tumor-induced disruption of whole-body homeostasis. Characterized by skeletal muscle atrophy and adipose tissue loss, cachexia leads to functional decline, impaired quality of life, reduced treatment tolerance, and poor survival across multiple malignancies. Emerging evidence indicates that cachexia arises from complex and dynamic interactions between tumors and host organ systems, including immune, metabolic, endocrine, and neural networks, that collectively reshape energy balance, immune function, and tissue integrity. Despite its profound clinical impact, effective therapies remain limited, reflecting incomplete mechanistic understanding and the absence of integrated clinical frameworks. Here, we review recent advances in cachexia biology, including tumor-host signaling, multiorgan metabolic remodeling, and neuroendocrine regulation. We further propose a tumor-centric framework in which cachexia represents a progressive collapse of systemic homeostasis and outline translational strategies to guide mechanism-informed therapeutic interventions.

Keywords:  adipose tissue loss; anorexia; cancer cachexia; energy balance; metabolic reprogramming; neuroendocrine regulation; skeletal muscle wasting; systemic inflammation; tumor-host interactions; whole-body homeostasis

DOI:  https://doi.org/10.1016/j.ccell.2026.03.012
Am J Physiol Cell Physiol. 2026 Apr 14.

Overactive PDGFRα and PDGFRβ promote distinct phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving muscle growth.

Mariola Gimla, Szczepan Olszewski, Jacob L Brown, Christiana J Raymond-Pope, Sandra Rigsby, Frederick F Peelor Iii, Hae Ryong Kwon, Longbiao Yao, Lorin E Olson, Jordan D Fuqua, Benjamin F Miller.

  Background: Fibrosis accumulates in skeletal muscle over time and leads to greater muscle rigidity, stiffness, and increased risk of injuries. However, investigations of appropriate experimental models to study the mechanisms through which muscle fibrosis occurs are often confounded by injury or disease. The contribution of platelet-derived growth factor receptors alpha and beta (PDGFRα or PDGFRβ) to muscle fibrosis is yet to be clarified. We hypothesized that both receptors would promote extracellular matrix (ECM) deposition and fibrosis, causing muscle stiffening and weakness, with sex-specific differences arising due to hormonal influences on receptors. Methods: To test this hypothesis, we used a mouse model with inducible overactive PDGFRα or PDGFRβ signaling and assessed various indicators of muscle function, metabolism, motor coordination, exercise capacity, collagen deposition, and muscle stiffness. Results: Overactive PDGFRα led to higher collagen deposition, collagen crosslinking, and AGE/LOX protein levels, all of which correlated with greater muscle stiffness compared to controls. Overactive PDGFRβ resulted in greater muscle mass and lower fat mass and had higher collagen deposition in female mice compared to controls. There were also sex-specific differences with fibrotic remodeling, muscle stiffness, and muscle size in response to overactive PDGFRα and PDGFRβ signaling. Conclusion: These findings establish PDGFRα and PDGFRβ signaling as distinct regulators of muscle remodeling and establish overactive PDGFRα as a mouse model to study skeletal muscle fibrosis in the absence of other confounding variables.

Keywords:  Collagen; Crosslinking; Isotope labelling; Muscle function; Muscle hypertrophy

DOI:  https://doi.org/10.1152/ajpcell.00035.2026
Autophagy. 2026 Apr 12.

Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.

Ang Li, Xianglu Xiao, Dajiang Qin, Huanxing Su.

  Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited. Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, has emerged as an attractive therapeutic target. In our recent study published in Pharmacological Research, we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.

Keywords:  Amyotrophic lateral sclerosis; Isoginkgetin; Lysosome; artificial intelligence; transcription factor EB

DOI:  https://doi.org/10.1080/15548627.2026.2659295
Cell Rep. 2026 Apr 09. pii: S2211-1247(26)00306-2. [Epub ahead of print]45(4): 117228

Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.

Cheng-Wei Hsieh, Guang-Chao Chen, Wei Yuan Yang.

  Cellular lysosomal capacity is tightly controlled to match catabolic demands and sustain lysosomal signaling pathways. Here, we report that cells can adjust their lysosomal capacity in response to varying autophagy loads. Manipulating the number of mitochondria targeted for mitophagy leads to a proportional upregulation of transcription factor EB (TFEB)-mediated lysosome adaptation programs. This quantitative control is exerted through Rag GTPase-driven mTORC1 suppression. GATOR1 is selectively recruited to lysosomes containing autophagic cargo, initiating local Rag GTPase-dependent suppression of mTORC1 activities. This mitophagy-induced mTORC1 suppression leads to TFEB activation and dephosphorylation of TOS-motif-containing substrates (S6K and 4EBP) under nutrient-rich conditions. This phenomenon similarly occurs during aggrephagy. These findings suggest that autophagic cargo-harboring lysosomes exhibit consistently low mTORC1 activity. Lysosomes can, therefore, sense the magnitude of autophagy loads and quantitatively translate this signal into TFEB activation to support self-regulated homeostasis.

Keywords:  CP: molecular biology; GATOR1; TFEB; aggregate autophagy; folliculin; lysosome; mTORC1; mitophagy

DOI:  https://doi.org/10.1016/j.celrep.2026.117228
J Physiol. 2026 Apr 14.

Oleuropein-based olive leaf extract enhances muscle mitochondrial bioenergetics response to moderate - but not maximal - intensity exercise in humans.

Clément Lanfranchi, Alba Moreno-Asso, Astrid M H Horstman, Sara Mistro, Eugenia Migliavacca, Ornella Cominetti, Jens Stolte, Sylviane Métairon, Aurélie Hermant, Ane Laura Pedersen, Loïc Dayon, Umberto De Marchi, Jérôme N Feige, Nadège Zanou, Nicolas Place.

  Sprint interval exercise (SIE) induces skeletal muscle mitochondrial adaptations that are comparable to, or greater than, those observed with moderate-intensity continuous exercise (MICE), despite requiring a lower training volume. Previous work has shown that these adaptations are at least partly mediated by enhanced mitochondrial bioenergetics, including increased mitochondrial Ca2+ uptake and resulting pyruvate dehydrogenase (PDH) activation. In parallel, the natural compound oleuropein from olive leaf extract (OLE) promotes mitochondrial Ca2+ uptake and activates PDH in mouse skeletal muscle. Here, we tested the hypothesis that OLE intake would activate PDH and potentiate mitochondrial adaptations in human skeletal muscle during either MICE or SIE. In a crossover, double-blind study, healthy males performed MICE (1 h at 50% maximal aerobic power, n = 11) or SIE (6 × 30 s all-out sprints with 4 min recovery, n = 10). Knee extensor neuromuscular tests and vastus lateralis muscle biopsies were performed before, immediately after and 24 h after SIE or MICE. OLE improved the decline of power output during the first sprint in SIE and reduced heart rate during MICE but did not affect knee extensor fatigability after both exercise modalities. Transcriptomic analyses revealed an effect of OLE on the mitochondrial and inflammatory response after MICE and SIE, while OLE increased PDH activity in combination with exercise only following MICE. Together, these results suggest that OLE modulates skeletal muscle response to exercise and pave the way for future investigations aiming to investigate the chronic effect of combining OLE and exercise training. KEY POINTS: Previous studies have shown that oleuropein increases mitochondrial calcium uptake in preclinical models and that mitochondrial calcium uptake contributes to skeletal muscle mitochondrial adaptations in response to maximal intensity exercise in humans. Olive leaf extract (OLE) increases the activity of pyruvate dehydrogenase, a proxy of mitochondria calcium uptake, when combined with moderate-intensity exercise. Combining moderate-intensity continuous exercise and sprint interval exercise with OLE enhances the mitochondrial response at a transcriptional level. OLE enhances skeletal muscle mitochondrial response to acute exercise, paving the way for investigating its effect in combination with chronic exercise training protocols.

Keywords:  calcium mitochondria; muscle fatigue; oxidative phosphorylation; power output; pyruvate dehydrogenase

DOI:  https://doi.org/10.1113/JP290316
Mol Metab. 2026 Apr 13. pii: S2212-8778(26)00051-7. [Epub ahead of print] 102367

BCL6 regulates skeletal muscle mass and mitochondrial bioenergetics.

Shirine E Usmani, Jean-Philippe Leduc-Gaudet, Stephanie Chau, Catherine A Bellissimo, Shabana Vohra, Krystel Desjardins, Evan Pollock-Tahiri, Irisa Shi, Felice Chun, Anthony Capobianco, Pascale Delisle, Wanda Dupebe, Marina Cefis, Vincent Marcangeli, Martha Ghebreselassie, Yu-Cheng Liang, Yasufumi Seki, Dominique Mayaki, Sabah Hussain, Ewan Goligher, Mohit Kapoor, Marius Locke, Gilles Gouspillou, Minna Woo.

  The transcriptional repressor B cell lymphoma 6 (BCL6) is highly expressed in skeletal muscle. Although transcriptome-wide studies have shown BCL6 dysregulation in muscular dystrophies, investigations into its endogenous roles in muscle biology remain scarce. We therefore generated skeletal muscle-specific Bcl6 knockout (M-Bcl6 KO) mice and used adeno-associated virus to knockdown (KD) Bcl6 selectively in limb muscles of mice. In both models, Bcl6 deficiency led to reduced muscle mass and contractility. Single-nucleus RNA sequencing and biochemical analyses revealed upregulation of Socs2, and inhibition of the IGF1/AKT pathway. Mitochondrial respiration was significantly reduced in permeabilized myofibers upon Bcl6 KO and KD, and electron microscopy showed decreased mitochondrial density and altered morphology. Pathways regulating mitochondrial quality control were also downregulated. While Bcl6 KO did not significantly impair baseline treadmill running capacity, it blunted the adaptive response to endurance training. These findings demonstrate that Bcl6 is a critical regulator of skeletal muscle mass and mitochondrial bioenergetics, acting through transcriptional control of signaling and metabolic pathways essential for the maintenance of muscle mass and function.

Keywords:  BCL6; endurance training; mitochondria; muscle atrophy; oxidative phosphorylation; respiration; skeletal muscle; weakness

DOI:  https://doi.org/10.1016/j.molmet.2026.102367
Aging Cell. 2026 Apr;25(4): e70485

Single-Nucleus RNA Sequencing Reveals Muscle Fiber Cell Heterogeneity During Human Skeletal Muscle Aging.

Caixia Gong, Li Wu, Ange Wang, Nan Hua, Chengfan Qin, Shunmei Huang, Xia Zhang, Yunmei Yang, Jing Chen, Qin Zhang.

  Aging impairs skeletal muscle mass and function, but the cell-type-resolved transcriptional states and intercellular signaling changes in human muscle aging remain incompletely mapped. Here, we constructed a single-nucleus RNA sequencing (snRNA-seq) atlas of human vastus lateralis muscle from adult (22-60 years) and elderly (99-101 years) male donors. We identified a comprehensive cellular census and discovered a profound reorganization of the myofiber transcriptional landscape. Aging was characterized by a shift from robust "young" states (MYLK4+ type II, LRP1B+ type I fibers) to dysfunctional "old" states (RYR3+ type II, RYR3+ type I fibers), accompanied by a marked emergence of hybrid fiber subtypes. We mechanistically linked these hybrid fibers to key aging pathologies: RUNX1+ hybrid fibers displayed a transcriptional signature of denervation, while SAA1+ hybrid fibers exhibited features of fatty infiltration, correlated with an expansion of fibro/adipogenic progenitors (FAPs). Pseudotime trajectory analysis supported the progression from young to degenerative or adipogenic fates. The aged microenvironment was globally altered, featuring impaired metabolic activity in muscle stem cells, compromised immune surveillance and function decline of vascular compartments. Critically, cell-cell communication analysis revealed enhanced BMP and Laminin signaling from FAPs to myofibers in aged tissue. Our work provided a high-resolution roadmap of human skeletal muscle aging, establishing denervation and FAP-driven fatty infiltration as key cellular mechanisms driving functional decline, and revealing novel targets for therapeutic intervention.

Keywords:  denervation; fatty infiltration; muscle fiber types; single‐nucleus RNA sequencing; skeletal muscle aging

DOI:  https://doi.org/10.1111/acel.70485
Age Ageing. 2026 Apr 04. pii: afag088. [Epub ahead of print]55(4):

Muscle mass, function and performance across the adult lifespan: the study of muscle, mobility and ageing.

Megan Hetherington-Rauth, Charles E McCulloch, Stephen B Kritchevsky, Anne B Newman, Russel T Hepple, Paul M Coen, Bret H Goodpaster, Mahalakshmi Shankaran, Marc Hellerstein, William J Evans, Frederico G S Toledo, Nancy E Lane, Peggy M Cawthon.

   BACKGROUND: D3-creatine (D3Cr) dilution provides an accurate estimate of total body skeletal muscle mass, yet few studies have examined its relationship with function and performance across the lifespan, particularly before age 70. We modelled the association of age with D₃Cr muscle mass across adulthood and compared it with age-related differences in muscle function and performance.
METHODS: Adults aged 30-69 years (n = 69; 33 men) and 70+ (n = 826; 344 men) from the Study of Muscle, Mobility and Ageing completed assessments of D3Cr muscle mass, magnetic resonance imaging (MRI) thigh muscle volume, 1-RM leg strength and leg extension power, 4 m walking speed and cardiorespiratory fitness (VO2 peak). Regression models estimated annualised percent differences with age for each outcome.
RESULTS: In men, progressively lower D₃Cr muscle mass with advancing age (-0.5%/year in young adults to -1.4%/year in oldest-old) paralleled the pattern observed for leg strength and walking speed (P > .05). Larger age-associated differences were observed for leg power and VO₂ peak, and smaller for MRI thigh muscle volume. In women, D₃Cr muscle mass was already lower in young adulthood (-0.6%/year) and remained relatively stable thereafter, a pattern similar to MRI thigh muscle volume. However, age-related differences in strength, power and VO₂ peak in women generally exceeded those in D₃Cr muscle mass, while walking speed aligned more closely.
CONCLUSION: Age-associated differences in muscle mass tracked closely with strength (men) and functional capacity. These results indicate that the role of low muscle mass in functional decline has been underestimated, emphasising the importance of strategies to preserve/enhance muscle mass throughout adulthood.

Keywords:  aerobic capacity; ageing; magnetic resonance imaging; older people; power; strength; walking speed

DOI:  https://doi.org/10.1093/ageing/afag088
Sci Adv. 2026 Apr 17. 12(16): eady8401

Multitissue, multi-time point transcriptomic atlas of aging in mice and rats.

Tea Shavlakadze, Kun Xiong, Romain Donne, Corissa McEwen, Abhilash Gadi, Matthew Wakai, Hunter Salmon, Jacob Treinish, Elias Pavlopoulos, Larry Proctor, Shuo Li, Nicole Negron, Min Ni, Yi Wei, Yu Bai, David J Glass.

To determine the genes and pathways that are up- or down-regulated in a consistent manner throughout the rodent lifespan, we generated a high N age-related gene expression atlas in mice and rats, by profiling 28 tissues in male and female C57BL/6J mice and 32 tissues in male Sprague Dawley rats (>5000 samples) over multiple time points. We identified age-related genes and pathways that change either early in life, at mid-age, late in life, or linearly throughout the animals' lifespan. Linear genes dominated many but not all tissues, and certain tissues were relatively spared from age-related changes. We explored common and different features of aging between tissues, sexes, and species. Given the expanse of our transcriptomic dataset, we believe that this study will serve as a useful resource for understanding the timing, tissue specificity, sex-specificity, and species specificity of age-related gene and pathway changes in mice and rats.

DOI: https://doi.org/10.1126/sciadv.ady8401
Redox Biol. 2026 Mar 09. pii: S2213-2317(26)00113-8. [Epub ahead of print]93 104115

Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans.

Marina Valenzuela-Villatoro, Patricia de la Cruz-Ruiz, David Guerrero-Gómez, Eva Gómez-Orte, Alfonso Schiavi, Silvia Maglioni, Mayte Montero, Rosalba I Fonteriz, José Carlos Casas-Martínez, Nicole E Briand, Jingxiu Xu, María Jesús Rodriguez-Palero, Marta Artal-Sanz, Katarzyna Olek, Justyna Polaczyk, Michal Turek, Wojciech Pokrzywa, Suhong Xu, Javier E Irazoqui, Brian McDonagh, Javier Álvarez, María Olmedo, Natascia Ventura, Juan Cabello, Antonio Miranda-Vizuete.

  Mitochondrial redox homeostasis is essential for cellular metabolism and organismal development. To investigate the consequences of disrupting redox homeostasis in this organelle in a metazoan organism, we generated a double mutant lacking mitochondrial glutathione reductase (gsr-1a) and thioredoxin reductase (trxr-2) genes in Caenorhabditis elegans. While gsr-1a or trxr-2 single mutants are phenotypically normal, double gsr-1a trxr-2 mutants displayed small body size, gonadal migration defects, reduced brood size, and prolonged egg-laying period, without developmental delay or lethality. Transcriptomic analysis revealed strong induction of ATFS-1-dependent stress and detoxification genes. Consistent with this, gsr-1a trxr-2 worms exhibited constitutive ATFS-1 nuclear localization and robust Phsp-6::gfp expression. Triple gsr-1a trxr-2; atfs-1 mutants were nonviable, demonstrating that unfolded protein response (UPRmt) activation is essential under mitochondrial redox stress. Despite the induction of a stress response at the transcriptional level, gsr-1a trxr-2 double mutants were not more resistant to oxidative or pathogen stressors. Moreover, these mutants maintained normal respiration, ATP and ROS production while displaying altered mitochondrial morphology in a tissue-specific manner, independent of mitophagy genes but dependent on mitochondrial fission or fusion machinery. Functionally, gsr-1a trxr-2 mutants showed impaired motility, reduced calcium uptake upon carbachol stimulation, enhanced hypodermal wound repair, and decreased fertilization efficiency associated with lower muscle exopher production. Overall, our data show that simultaneous loss of mitochondrial GSR-1a and TRXR-2 compromises growth, fertility and muscle performance and triggers a constitutive ATFS-1-dependent UPRmt that sustains viability revealing mitochondrial redox control as a core determinant of organismal proteostasis.

Keywords:  ATFS-1; Elegans; Glutathione reductase; Mitochondria; Thioredoxin reductase; Unfolded protein response

DOI:  https://doi.org/10.1016/j.redox.2026.104115
Cancers (Basel). 2026 Mar 25. pii: 1060. [Epub ahead of print]18(7):

Pathogenesis, Diagnostic Pathways, and New Therapeutic and Nutritional Strategies for Pancreatic Cancer-Associated Cachexia.

Wiktoria Klus, Jagoda Ossowska, Katarzyna Kowalcze, Anna Kiliszczyk, Agnieszka Paziewska.

  Background/Objectives: Pancreatic cancer-associated cachexia (CAC) is a complex, multifactorial and multi-organ metabolic syndrome affecting approximately 80% of patients with pancreatic ductal adenocarcinoma (PDAC). Recent epidemiological data show that cachexia is a primary cause of mortality in PDAC, directly accounting for approximately 30% of cancer-related deaths and significantly limiting the tolerability of cancer therapy and is associated with adverse effects of treatment. It is defined by systemic weight loss, skeletal muscle atrophy (sarcopenia), and adipose tissue depletion, often driven by systemic inflammation and metabolic dysregulation. Methods: The literature was searched in PubMed and Scopus using combinations of keywords. The search covers the literature between 2016 and 2026, but papers before this period were also included because of their historical importance. Studies with higher evidential value, such as prospective studies, randomized controlled trials, and meta-analyses, were prioritized and emphasized in our analysis. Results: CAC in PC arises from a systemic inflammatory response driven by tumor-host interactions and the release of pro-inflammatory mediators, such as growth differentiation factor 15 (GDF-15) and parathyroid hormone-related protein (PTHrP), which promotes anorexia and weight loss. The most commonly used diagnostic criteria include unintentional weight loss of more than 5% of body mass within 6 months, a body mass index (BMI) below 20 kg/m2, or weight loss greater than 2% in the presence of sarcopenia. Emerging evidence supports the use of AI-based body composition analysis and novel biomarkers, including GDF-15 levels, to improve the detection and monitoring of cachexia. This review highlights that, despite the absence of pharmacological agents specifically approved for CAC in the United States and Europe, current guidelines recommend multimodal supportive care, including low-dose olanzapine, nutritional support, and exercise-based interventions. Furthermore, we identify recent phase 2 trials targeting the GDF-15 pathway, such as the GDF-15 inhibitor ponsegromab, which have demonstrated significant improvements in body weight and physical activity, suggesting a potential breakthrough in targeted therapies for CAC. Conclusions: CAC in PDAC represents a critical unmet medical need in oncology. It manifests as a lethal systemic pathology that demands early identification and targeted personalized pharmacological and nutritional interventions. Early diagnosis and targeted intervention represent promising strategies for improving survival and quality of life in this high-risk patient population.

Keywords:  PEI; PERT; cachexia; inflammation; metabolism; microbiome; pancreatic cancer

DOI:  https://doi.org/10.3390/cancers18071060
Mol Neurobiol. 2026 Apr 13. pii: 559. [Epub ahead of print]63(1):

Up-regulation of miR-548 m Leading to Neuroinflammation to Promote the Progression of Alzheimer's Disease.

Minxia Zhan, Gang Liu, Yu-Mei Liu, Bochu Wang.

  Neuroinflammation mediated by microglia is recognized as a critical contributor to Alzheimer's disease (AD) pathogenesis, and P2RY12 maintains microglial homeostasis. MicroRNAs regulate gene expression post-transcriptionally and have been implicated in modulating microglial activation states during AD by affecting inflammatory pathways. This study aimed to investigate the role of miR-548 m in regulating microglial polarization and neuroinflammation in Alzheimer's disease. Male APP/PS1 transgenic and wild-type mice were utilized as animal models alongside cultured microglial cells for in vitro studies. Behavioral assessments, including contextual fear Morris water maze (MWM) and fear conditioning (FC), evaluated cognitive function. Molecular analyses comprised RT-qPCR western blot, and ELISA, as well as dual-luciferase reporter assays to validate miR-548 m and P2RY12 interactions. In vivo modulation of miR-548 m expression was achieved via stereotaxic intracerebral injections of agomir or antagomir oligonucleotides targeting the dentate gyrus. MiR-548 m was significantly upregulated in AD. Overexpression of miR-548 m promoted microglial M1 polarization characterized by increased pro-inflammatory cytokines (TNF-α, IL-6, iNOS, IL-1β) and reduction in M2 anti-inflammatory markers (Arg1, CD206, IL-4, TGF-β). Inhibition of miR-548 m improved spatial learning and memory performance while attenuating microglial activation in vivo. Luciferase reporter assays confirmed that P2RY12 is a direct downstream target suppressed by miR-548 m. And overexpression of miR‑548 m reversed the inflammatory effects induced by P2RY12 overexpression. These findings demonstrate that elevated miR‑548 m exacerbates neuroinflammation through negative regulation of P2RY12 expression, leading to enhanced microglial M1 polarization during AD progression. Targeting the miR‑548 m/P2RY12 axis may provide a novel therapeutic for mitigating AD.

Keywords:  Alzheimer’s disease; M1/M2 polarization; MiR-548 m; Microglial; Neuroinflammation; P2RY12

DOI:  https://doi.org/10.1007/s12035-026-05809-9
Biofabrication. 2026 Apr 15.

Development of a spatially defined 3D in vitro coculture construct modelling pancreatic cancer-associated cachexia.

Mitchell A Kuss, Mena Asha Krishnan, Wonmi So, So-Youn Kim, Bin Duan.

  Pancreatic cancer-associated cachexia is marked by adipose tissue wasting, thermogenic remodeling, and a state of hypermetabolism, yet robust preclinical models to study these phenomena are lacking. In this study, we present a spatially defined three-dimensional (3D) coreshell microcuboid coculture platform designed to investigate the interaction between adipocytes and pancreatic cancers. This innovative system consists of differentiated white adipocytes at the core, surrounded by pancreatic ductal adenocarcinoma (PDAC) cells embedded in 3D-printed microcuboids, arranged concentrically within a collagen coculture matrix construct. Within this framework, we observed significant enhancement of adipocyte lipolysis and browning, as evidenced by BODIPY dye-tracked lipid migration, sustained glycerol release, and progressive expression of extracellular UCP1 or the mitochondrial brown fat uncoupling protein 1, particularly pronounced in cocultures involving aggressive pancreatic cancer cell lines. The integrity of the core-shell architecture persisted for up to 21 days but progressively disintegrated under the influence of the cancer cells marked by cancer cell invasion into the adipocyte regions. Gene profiling revealed a downregulation of adipogenic markers, such as Pparg, Plin1, and Lipe, alongside an increase in Ucp1 transcripts, suggesting a metabolic shift from lipid storage to utilization and thermogenic activation. In contrast to existing 3D engineered systems, our platform offers enhanced long-term viability, controlled compartmentalization, mechanical tunability, and high spatiotemporal resolution. It effectively recapitulates the dynamic interplay between cancer and adipose cells, along with the catabolic characteristics of PDAC-associated cachexia, serving as a scalable in vitro tool for mechanistic investigations, and for testing potential anti-cachexia interventions, filling the gap between simplistic in vitro assays and complex animal models.

Keywords:  3D modelling; Cancer cachexia; UCP1 expression; adipocyte; cancer-adipocyte crosstalk; cell migration

DOI:  https://doi.org/10.1088/1758-5090/ae5fda
Osteoporos Sarcopenia. 2026 Mar;12(1): 44-50

Sarcopenic obesity and sarcopenia in relation to frailty, independent of locomotive syndrome: the DETECt-L cross-sectional study.

Naoki Deguchi, Tomoyuki Akita, Yasushi Uchiyama, Ryo Tanaka.

   Objectives: Frailty among community-dwelling older adults increases the risk of adverse health outcomes. Sarcopenic obesity (SO), characterized by low muscle mass combined with excess adiposity, may worsen frailty. Locomotive syndrome (LS) shares features with frailty and sarcopenia. This study examined whether LS modifies the association between body composition and frailty.
Methods: We analyzed cross-sectional data of 481 adults aged ≥ 40 years from the DETECt-L cohort in Japan. Frailty was defined according to the Japanese Cardiovascular Health Study criteria. Body composition was measured using bioelectrical impedance, based on skeletal muscle mass and body fat, to categorize participants into normal, sarcopenia, obesity, or SO phenotypes. Logistic regression-estimated odds ratios for comparing prefrailty/frailty with robustness were calculated. Model 1 was unadjusted; Model 2 (fully adjusted) adjusted for age, sex, pain, fall history, and Timed Up-and-Go and single-leg standing tests; and Model 3 additionally included body mass index (BMI) (sensitivity).
Results: Overall, 41.6% of participants were classified as prefrail or frail. The distribution of body composition phenotypes was as follows: normal (42.8%), sarcopenic (31.2%), obese (15.8%), and SO (10.2%). In Model 2, both sarcopenia (odds ratio [OR], 2.24; 95% confidence interval [CI], 1.38-3.63) and SO (OR, 2.51; 95% CI, 1.21-5.24) were associated with increased odds of prefrailty/frailty. These associations remained robust after adjusting for BMI. However, LS did not significantly affect these associations.
Conclusions: Sarcopenia and SO were independently associated with prefrailty/frailty regardless of LS status. Integrating muscle function and adiposity metrics may support early risk detection in community settings.

Keywords:  Community-dwelling adults; Frailty; Locomotive syndrome; Sarcopenia; Sarcopenic obesity

DOI:  https://doi.org/10.1016/j.afos.2025.11.003
bioRxiv. 2026 Apr 11. pii: 2026.04.09.717568. [Epub ahead of print]

Whole-organism spatial transcriptomics at single-cell resolution in C. elegans.

Jose David Aguirre Aguilera, Xuan Wan, Carsten H Tischbirek, Core Francisco Park, Long Cai, Paul W Sternberg.

Spatial transcriptomics has advanced our understanding of tissue organization by mapping gene expression in its native context yet applying these techniques to whole organisms remains a significant challenge. Caenorhabditis elegans is well-suited to whole organism-level analysis because its compact size, transparency, reproducible anatomy, and genetic tractability make it possible to link molecular and cellular changes to circuit function and behavior within the same animal. However, current transcriptomic approaches in C. elegans are often limited by spatial resolution or multiplexing capacity, making it challenging to profile multiple gene expression patterns across intact worms while preserving spatial context. Here, we present a single-molecule fluorescence in situ hybridization workflow that enables multiplex imaging with single-cell resolution across the entire worm. This approach allows sequential imaging of one gene per fluorescent channel using two channels across 20 hybridization rounds, enabling the profiling of up to 40 genes while preserving spatial context. We further provide a curated marker-gene panel for reproducible neuron identification, which, together with probabilistic assignment of transcripts to segmented nuclei, enables quantitative measurements of gene expression levels. We used this method to identify up to 86 neuronal classes and reveal sex- and neuron-specific expression patterns at single-cell resolution. Together, these results establish a scalable framework for the spatial analysis of gene expression and cell identity in intact C. elegans .

DOI: https://doi.org/10.64898/2026.04.09.717568
Elife. 2026 Apr 17. pii: RP107332. [Epub ahead of print]14

Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle.

Yibo Fan, Senuri De Silva, Nishat I Tabassum, Xiangyuan Peng, Vernise J T Lim, Xiangru Cheng, Keshava K Datta, Rohan Lowe, Terrance G Johns, Mark P Mattson, Suresh Mathivanan, Christopher G Sobey, Eitan Okun, Yong U Liu, Guobing Chen, Mitchell Kim Peng Lai, Dong-Gyu Jo, Jayantha Gunaratne, Thiruma V Arumugam.

  Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

Keywords:  Serpin A1c; bioinformatics; cell biology; intermittent fasting; medicine; metabolic reprogramming; mouse; proteomics; transcriptomics

DOI:  https://doi.org/10.7554/eLife.107332