bims-musmir 2026-03-15 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–03–15
seventeen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Circulating Musclin is associated with skeletal muscle function and subclinical cardiac dysfunction in patients with cancer.
Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.
Pancreatic cancer-associated organ dysfunction promotes muscle autophagy and contributes to peripheral tissue wasting.
cAMP and mitochondrial dysfunction in cancer cachexia.
OGG1 increases exercise endurance via elevated skeletal muscle FGF21.
Changes in human multifidus muscle size with aging and short-term disuse.
A Novel Competing Endogenous RNA Linked to Dysregulated Neuroinflammation in Alzheimer's Disease.
Collagen gene expression is linked to aging and lifespan extension in C. elegans.
Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis.
Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort.
PARK19 truncation mutant Dnajc6 causes lysosomal deficiency-induced upregulation of pathologic α-synuclein and neurodegeneration of substantia nigra dopaminergic cells in PARK19 knockin mice.
Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
cGAS inhibition delays TDP-43-driven ALS Pathogenesis.
Bidirectional Regulation between Metabolic Dysfunction-associated Steatotic Liver Disease and Sarcopenia via Liver-muscle Crosstalk.
ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.
Aged Male Mice Remain Glucose Tolerant Despite Increased Energy Storage Efficiency Favoring Diet-Induced Obesity.
Ginkgetin alleviates cisplatin-induced muscle atrophy via inhibition of the macrophage cGAS-STING pathway.

Br J Pharmacol. 2026 Mar 13.

Circulating Musclin is associated with skeletal muscle function and subclinical cardiac dysfunction in patients with cancer.

Jannek Brauer, Daniel Finke, Sebastian Romann, Norbert Frey, Joerg Heineke, Lorenz H Lehmann.

   BACKGROUND AND PURPOSE: Musclin (osteocrin) is a skeletal muscle-derived peptide that has been implicated in cardioprotective signalling pathways. Its relevance in cancer patients, who frequently experience muscle wasting and cardiotoxicity, remains unclear. This study aimed to determine whether circulating Musclin levels reflect functional capacity and cardiovascular risk in a cardio-oncology population.
EXPERIMENTAL APPROACH: We prospectively evaluated circulating Musclin levels in cancer patients (n = 69) undergoing standardised cardiovascular assessment during oncologic therapy. Echocardiographic measures of cardiac function, anthropometric and functional indices of muscle integrity, oncologic stage and clinical outcomes were analysed to identify associations with Musclin exposure over time.
KEY RESULTS: Lower circulating Musclin levels were associated with a reduced survival probability in exploratory analyses (log-rank P = 0.046), decreased physical performance (hand grip strength), and features of advanced malignancy. Patients with higher cumulative Musclin levels showed significantly better cardiac functional parameters (global longitudinal strain) (P = 0.031). Musclin serum concentrations also reflected indicators of skeletal muscle function that were not captured by weight-based metrics.
CONCLUSION AND IMPLICATIONS: Circulating Musclin may reveal information on skeletal muscle integrity and subclinical cardiac dysfunction, identifying cancer patients at increased functional and prognostic risk. These findings support Musclin as a biologically plausible and clinically relevant biomarker at the interface of muscle-heart signalling.

Keywords:  Musclin; body composition; cancer cachexia; cardiotoxicity; cardio‐oncology

DOI:  https://doi.org/10.1111/bph.70404
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70237

Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.

Cui Wang, Lin Gao, Rui Xue, Jia Su, Honghui Li, Wei Yang, Yan Tang, Zhihang Su, Shasha Min, Changyong Tang, Yuqi Zhu, Bo Mu, John R Speakman, Xina Xie, Zesong Li.

   BACKGROUND: Cancer cachexia is a multifactorial wasting syndrome marked by profound skeletal muscle loss. Tumours can release high levels of Activin A (ActA), which activates the ubiquitin-proteasome pathway (UPP) and drives muscle wasting. Systemic blockade of the ActA pathway is associated with inflammatory adverse effects, and tumour-restricted targeting alone often fails to reverse cachexia. We asked whether ActA produced by host (nontumour) organs contributes to circulating ActA and muscle wasting.
METHODS: We profiled ActA across tissues and in serum in Lewis lung carcinoma (LLC) cancer cachexia mice to generate an organ-wide expression map. Functional studies were then performed using adeno-associated-virus (AAV)-knockdown in the heart (cTnT/hTCF21 promoters) and kidney (CMV promoter), followed by cachexia induction. Body weight (BW), food intake, skeletal muscle mass, muscle function and muscle histomorphology were assessed. Mitochondrial ultrastructure and lipid metabolic pathways in muscle and adipose tissue were also examined.
RESULTS: LLC cachexia mice exhibited significant reductions in body weight (-6.0%, p < 0.05), food intake (-9.9%, p < 0.05), quadriceps mass (-15.3%, p < 0.05) and grip strength (-13.0%, p < 0.0001) compared with non-tumour-bearing (NTB) mice (n = 6-12/group). ActA expression was markedly increased in the host organs, particularly in the kidney (2.8-fold vs. NTB, p < 0.001) and heart (2.7-fold vs. NTB, p < 0.05) (n = 10/group). Compared with the sh-NC, organ-targeted ActA knockdown restored body weight (+6.1%, p < 0.05) and food intake (+8.4%, p < 0.05), increased quadriceps mass (+17.2%, p < 0.05) and grip strength (+10.7%, p < 0.01), reduced intramuscular fat infiltration and attenuated UPP signalling (n = 8-16/group). These effects were accompanied by increased expression of the mitochondrial fatty-acid oxidation regulator carnitine palmitoyltransferase 1B (CPT1B) (+42.3% of mRNA level; +30.9% of protein level; both p < 0.05) and CPT2 (+57.7% of mRNA level, p < 0.05), improved mitochondrial ultrastructure and partial restoration of adipose mass.
CONCLUSIONS: Simultaneous downregulation of Activin A in the kidney and heart attenuates skeletal muscle atrophy and intramuscular adipogenesis, improves muscle mass and function and mitigates adipose tissue mass loss in cancer cachexia mice. These findings identify heart- and kidney-derived Activin A as a key driver of cachexia, which acts through a combinatorial effect rather than an isolated contribution from either one alone, highlighting its potential as a therapeutic target.

Keywords:  Activin A; cancer cachexia; heart and kidney; intramuscular fat infiltration; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70237
bioRxiv. 2026 Mar 01. pii: 2026.02.27.708635. [Epub ahead of print]

Pancreatic cancer-associated organ dysfunction promotes muscle autophagy and contributes to peripheral tissue wasting.

Yetiş Gültekin, Sharanya Sivanand, Kian M Eghbalian, Anna M Barbeau, Keene L Abbott, George Eng, Victoria L Tavernier, Brian T Do, Heaji Shin, Elif Özçelik, Sabrina Hu, Tenzin Kunchok, Millenia Waite, William M Rideout, Yiğit K Kizlier, Daniel A Sharygin, William A Freed-Pastor, Tyler Jacks, Eileen White, Ömer H Yilmaz, Jonathan A Nowak, Brian M Wolpin, Matthew G Vander Heiden.

Normal pancreas function supports both digestion and the hormonal regulation of whole-body metabolism. We find pancreatic ductal adenocarcinoma (PDAC) disrupts the normal function of the remaining pancreas, leading to altered systemic metabolism and peripheral tissue wasting that begins early in disease progression. Using mouse models of PDAC, we find small pancreas tumors lead to both endocrine and exocrine pancreatic dysfunction that results in systemic nutrient depletion and loss of both muscle and fat tissue. Providing free glucose in the diet that is absorbed despite pancreatic exocrine dysfunction causes hyperglycemia and blunts fat wasting without affecting muscle loss. Muscle mass can be restored by free dietary amino acids or pancreatic enzyme supplementation. Exocrine dysfunction causing reduced dietary protein digestion promotes muscle proteolysis and autophagy. Autophagy is a major driver of muscle wasting in PDAC, as muscle-specific deletion of the core autophagy gene Atg7 also reduces muscle wasting. Disrupting muscle autophagy without restoring systemic nutrition slows tumor growth and improves survival of mice with PDAC. Tracing the fate of amino acids released from muscle of mice with PDAC shows redistribution to both tumor and host tissues. Notably, improving nutrition in mice with disrupted muscle autophagy promotes tumor growth. Together, the data argue that early peripheral tissue wasting associated with early pancreatic cancer is driven by altered normal pancreatic organ function that leads to reduced nutrition and enhanced muscle autophagy, releasing nutrients to support both tumor and host metabolism.

DOI: https://doi.org/10.64898/2026.02.27.708635
Trends Mol Med. 2026 Mar 12. pii: S1471-4914(26)00013-4. [Epub ahead of print]

cAMP and mitochondrial dysfunction in cancer cachexia.

Itamar C G Jesus, Julio C B Ferreira.

  A recent study by Angelino et al. uncovered an intracellular signaling pathway involved in musculoskeletal mitochondrial dysfunction in cancer cachexia. Both humans and mice with cancer cachexia display impaired 3',5'-cyclic adenosine monophosphate (cAMP)-protein kinase A-cAMP response element-binding protein 1 signaling, which leads to mitochondrial dysfunction. By rescuing this pathway with a phosphodiesterase-4 inhibitor, the authors highlight a potential therapeutic strategy for cancer cachexia.

Keywords:  PDE4D; cAMP; cancer cachexia; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.molmed.2026.01.009
J Biol Chem. 2026 Mar 09. pii: S0021-9258(26)00230-9. [Epub ahead of print] 111360

OGG1 increases exercise endurance via elevated skeletal muscle FGF21.

Bhavya Blaze, Priyanka Sharma, Bhavya Prakash Gupta, Souvik Mandal, Sai Santosh Babu Komakula, Tracy Anthony, Emmanuel Marfo, Harini Sampath.

  The base excision repair (BER) pathway maintains genomic integrity in the face of oxidative insult. It is initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1) and is implicated in various pathologies such as cancers and neurodegenerative disease. BER proteins also modulate body weight and metabolic health. Mice lacking OGG1 are susceptible to obesity and its sequelae, while overexpression of human OGG1 (in OGG1-transgenic; Ogg1Tg mice) reverses these metabolic defects. We report here that OGG1 overexpression induces a remarkable over 3-fold increase in muscle endurance. This is accompanied by significant increases in muscle mitochondrial content and size and a selective increase in expression of the myokine, Fgf21, in skeletal muscle of Ogg1Tg mice. Together with elevated circulating FGF21 levels and peripheral markers of FGF21 action, these data demonstrate a novel role for skeletal muscle OGG1 in modulating mitochondrial health and muscle endurance via FGF21 secretion and signaling.

Keywords:  base excision repair; exercise tolerance; fibroblast growth factor; mitochondria; myokine; skeletal muscle

DOI:  https://doi.org/10.1016/j.jbc.2026.111360
Exp Gerontol. 2026 Mar 07. pii: S0531-5565(26)00068-9. [Epub ahead of print]217 113090

Changes in human multifidus muscle size with aging and short-term disuse.

Fabio Sarto, Elena Monti, Sara Tagliaferri, Bostjan Simunič, Marco Salvi, Tereza Jandova, Martino V Franchi, Rado Pišot, Marcello Maggio, Marco V Narici.

  Lumbar multifidus (MF) muscle plays a key role in spinal stability, yet its adaptations to aging and disuse, which become increasingly prevalent with advancing age, remain unclear. We conducted two studies to investigate age- and inactivity-induced changes in MF size. In Study 1, we assessed 32 young adults (50% females) and 75 older adults (67% females), categorized as non-sarcopenic (NS) or probable sarcopenic (PS) based on EWGSOP2 criteria. In Study 2, we examined early MF responses to 10-day horizontal bed rest in 10 young males. MF cross-sectional area (CSA) and side-to-side asymmetry were measured using ultrasound imaging and compared with the vastus lateralis (VL) CSA. In Study 1, MF CSA was negatively associated with age (p < 0.0001) and probable sarcopenia, being lower in PS compared to NS (p = 0.012). MF showed larger effect sizes than VL [Y vs NS: MF g = 1.62, VL g = 1.35; Y vs PS: MF g = 2.48, VL g = 1.35]. MF asymmetry was greater in PS compared to Y (p = 0.003). In Study 2, bed rest induced early reductions in MF CSA (detectable by day 4, p = 0.047) without increasing asymmetry. In conclusion, the MF was smaller in older populations and decreased following short-term disuse, while greater asymmetry was observed only with aging. These findings suggest that the MF is a highly plastic muscle in response to aging and disuse and that its assessment may serve as a potential hallmark of muscle maladaptation in clinical and experimental settings.

Keywords:  Bed rest; Muscle atrophy; Paraspinal muscles; Physical inactivity; Sarcopenia; Ultrasound imaging; Unloading

DOI:  https://doi.org/10.1016/j.exger.2026.113090
Cells. 2026 Feb 27. pii: 412. [Epub ahead of print]15(5):

A Novel Competing Endogenous RNA Linked to Dysregulated Neuroinflammation in Alzheimer's Disease.

Dinesh Devadoss, Juliet Akkaoui, Natalia Orso, Thiruselvam Viswanathan, Glen M Borchert, Madepalli K Lakshmana, Hitendra S Chand.

  Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder in which dysregulated neuroinflammation drives disease progression. Although long noncoding RNAs (lncRNAs) are increasingly implicated in AD, their mechanistic roles remain poorly defined. Here, we identified a novel lncRNA termed LIMASI (LncRNA Inflammation and Mucous associated, Antisense to ICAM1), that is linked with AD-associated neuroinflammation. LIMASI expression is significantly elevated in postmortem AD brain tissues and in a 3xTg-AD mouse model by qPCR and RNA fluorescence in situ hybridization, and its upregulation is correlated with increased β-amyloid plaque burden, tau hyperphosphorylation, and heightened neuroinflammatory activation. Cell type-specific analyses demonstrated inflammation-inducible LIMASI expression in astrocytes and microglia. In an in vitro model of AD-associated neuroinflammation, viral mimetic poly(I:C) challenge of amyloid precursor protein (APP)-overexpressing neuroblastoma cells elicited coordinated induction of LIMASI and key inflammatory mediators. Mechanistically, we observed elevated levels of inflammatory microRNAs (miR-155-5p and miR-150-5p) in AD brain tissues, and computational modeling predicted energetically favorable interactions between these miRNAs and LIMASI. These findings support a competing endogenous RNA (ceRNA) model in which LIMASI sequesters pro-inflammatory miRNAs to modulate neuroinflammatory gene networks. Together, our data identify LIMASI as a putative ceRNA strongly associated with AD-related neuroinflammation and suggest that targeting LIMASI may represent a novel strategy to attenuate neuroinflammatory signaling and potentially slow AD-associated neurodegeneration.

Keywords:  Alzheimer’s disease (AD); competing endogenous RNA (ceRNA); long noncoding RNAs (lncRNAs); microRNAs (miRNAs); neuroinflammation

DOI:  https://doi.org/10.3390/cells15050412
Matrix Biol Plus. 2026 Jun;30 100192

Collagen gene expression is linked to aging and lifespan extension in C. elegans.

Archer J Wang, Blake M Geppert, Daniel Beck, Yanqing Ji, Yiyong Liu.

Collagens, long regarded as structural molecules, also regulate stress responses and longevity. In this study, we analyzed our RNA sequencing data and publicly available gene expression data to define their role in Caenorhabditis elegans aging. Collagen expression broadly declined with age, with 16 collagen genes consistently downregulated across independent studies, establishing collagen downregulation as a genetic hallmark of aging. In contrast, meta-analysis of 66 datasets (128 comparisons between normal and long-lived animals) showed collagen upregulation in 84% of long-lived conditions, identifying collagen induction as a conserved signature of lifespan extension. Using π-values to integrate fold change and significance of collagen gene expression, we applied K-means clustering and identified Euclidean-based clusters that captured functional, tissue-associated subsets of collagens. Notably, aging-associated collagens were strongly enriched in Euclidean Cluster 1, which overlapped with hypodermal collagens, while Cluster 2 significantly intersects with lifespan-extension and intestine-enriched subsets, and Cluster 3 likely represents structural collagens contributing to cuticle and muscle integrity. These results indicate that collagen genes grouped by expression-based clustering are not randomly distributed but instead reflect tissue-specific patterns and functionality. Together, our findings suggest that collagens are dynamic regulators of aging and longevity in C. elegans. Given the conservation of extracellular matrix biology across species, collagens represent candidate biomarkers and targets for promoting healthy aging in both C. elegans and higher animals.

DOI: https://doi.org/10.1016/j.mbplus.2026.100192
Neurol Genet. 2026 Apr;12(2): e200366

Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis.

Rogan G Magee, Vivianna M Van Deerlin, Corey T McMillan, Edward B Lee, Lauren B Elman, David John Irwin, Zissimos Mourelatos.

Background and Objectives: There are no FDA-approved diagnostic biomarkers for amyotrophic lateral sclerosis (ALS). TDP-43 is a known cofactor in the cleavage of long premature microRNAs (miRNAs) into their short, mature products. isomiRs are miRNA variants that differ in their 5' and 3' end points and regulate distinct mRNA targets. In this study, we tested the hypotheses that circulating isomiR profiles differ in the context of TAR DNA-binding Protein pathology and that isomiRs are superior to miRNAs for classification of ALS.
Methods: We obtained RNA from plasma samples of 14 patients with ALS and 14 age-matched and sex-matched controls for sequencing on a NextSeq 2000. Data were processed using Unique Molecular Identifier tools and a custom pipeline designed to match miRNA variant sequences without mismatches. Differential expression (DE) was identified using DEseq2 at FDR ≤ 0.1. XGBoost classifiers were built using a subset of (Model 1) isomiRs or (Model 2) miRNAs that were present above a median threshold in all sequencing batches. Parameters were tuned using grid search and 10-fold cross-validation while training to distinguish ALS samples from controls among a single large public data set. Models were then validated on in-house samples and 1 publicly available holdout data set.
Results: Fourteen (0.2%), 355 (2.7%), and 14 (0.7%) isomiRs were differentially expressed in in-house plasma, public ALS plasma, and public ALS serum, respectively. One (0.1%), 94 (5.5%), and 13 (2.4%) miRNAs were differentially expressed, respectively. Model 1 accurately classified in-house ALS plasma and public ALS serum (area under the curve [AUC] = 0.87) and did not distinguish 40 of 41 Alzheimer disease samples from control plasma (GSE215789; AUC = 0.47) or 60 of 77 Parkinson disease samples from control whole blood (GSE180193; AUC = 0.55). In comparison, Model 2 using miRNAs performed worse on in-house plasma (AUC = 0.49).
Discussion: Analyzing individual isomiRs may improve the performance of circulating noncoding RNAs as diagnostic biomarkers of ALS.

DOI: https://doi.org/10.1212/NXG.0000000000200366
Nat Aging. 2026 Mar 13.

Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort.

Pei-Lun Kuo, Ann Zenobia Moore, Toshiko Tanaka, Daniel W Belsky, Ake Tzu-Hui Lu, Steve Horvath, Stefania Bandinelli, Luigi Ferrucci.

Epigenetic clocks derived from DNA methylation patterns are among the most promising biomarkers of biological aging1-7, as they capture molecular signatures that predict morbidity and mortality beyond chronological age. Although cross-sectional assessments of epigenetic age have been linked consistently to health outcomes and lifespan, it remains unclear whether the rate of change in these clocks over time provides additional insight into aging trajectories. In this longitudinal study of 699 adults from the InCHIANTI cohort followed for up to 24 years, we evaluated whether temporal acceleration of several epigenetic clocks-including first-, second- and third-generation epigenetic clocks-was associated with mortality. We found that faster increases in several clocks were linked robustly to higher risk of death, independent of baseline epigenetic age and other confounders. These findings suggest that dynamic changes in epigenetic aging reflect evolving health status and may serve as sensitive indicators for interventions aimed at extending healthspan and longevity.

DOI: https://doi.org/10.1038/s43587-026-01066-6
NPJ Parkinsons Dis. 2026 Mar 12.

PARK19 truncation mutant Dnajc6 causes lysosomal deficiency-induced upregulation of pathologic α-synuclein and neurodegeneration of substantia nigra dopaminergic cells in PARK19 knockin mice.

Hung-Li Wang, Ying-Ling Chen, Tai-Ju Chiu, Ching-Chi Chiu, Yi-Hsin Weng, Shu-Yu Liu, Allen Hon-Lun Li, Tu-Hsueh Yeh.

Homozygous (Q789X) DNAJC6 mutation causes PARK19. Q787 of Dnajc6 corresponds to Q789 of DNAJC6. Dnajc6Q787X/Q787X mouse was utilized to elucidate pathomechanisms underlying (Q789X) DNAJC6-induced PARK19. Dnajc6Q787X/Q787X mice displayed PARK19 motor deficits and degeneration of substantia nigra (SN) dopaminergic neurons. (Q787X) Dnajc6 decreased clathrin heavy chain and lysosomal number, leading to downregulation of lysosomal cathepsin D and upregulation of α-synuclein or α-synuclein oligomers in SN dopaminergic neurons. Lysosomal biogenesis activator rapamycin precluded (Q787X) Dnajc6-induced downregulation of cathepsin D, upregulation of α-synuclein, and PARK19 phenotypes. (Q787X) Dnajc6-induced elevation of ER and mitochondrial α-synuclein excited ER stress and mitochondrial pro-apoptotic cascades. (Q787X) Dnajc6-evoked α-synuclein oligomer overexpression activated SN microglia and NLRP3 inflammasome and upregulated IL-1β, IL-18, and TNF-α, which stimulated MKK4-JNK -c-Jun/ATF-2 and RIPK1-RIPK3-MLKL death cascades. Our results suggest that PARK19 (Q789X) DNAJC6 mutation causes lysosomal deficiency and impairs cathepsin D-mediated degradation of α-synuclein, resulting in upregulated α-synuclein-induced neurodegeneration of SN dopaminergic cells.

DOI: https://doi.org/10.1038/s41531-026-01317-8
bioRxiv. 2026 Feb 28. pii: 2026.02.26.708335. [Epub ahead of print]

Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.

Seungmin Yoo, Christopher Young, Liying Li, Lingraj Vannur, Junming Zhuang, Fan Zheng, Meiying Wu, Julie K Andersen, Chuankai Zhou.

Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.

DOI: https://doi.org/10.64898/2026.02.26.708335
bioRxiv. 2026 Feb 26. pii: 2026.02.24.707791. [Epub ahead of print]

cGAS inhibition delays TDP-43-driven ALS Pathogenesis.

Yajing Liu, Weixi Feng, Abulimiti Aikedan, Se-In Lee, Maitreyee Bhagwat, Ravi Kumar Nagiri, Man Ying Wong, Sadaf Amin, Wenhui Qu, Jingjie Zhu, Si-Yu Wang, Pearly Ye, Kendra Norman, Guillermo Coronas-Samano, Marta Olah, Hagen U Tilgner, Li Fan, Subhash C Sinha, Li Gan.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by motor neuron loss and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA splicing. However, the upstream modulators of this process remain poorly defined. Here we identify cyclic GMP-AMP synthase (cGAS) as a central mediator of TDP-43 pathology and associated mis-splicing. cGAS expression was elevated in ALS patient brains and enriched across activated microglia. In human iPSC-derived microglia-motor neuron co-cultures, neuronal TDP-43 pathology triggered microglial cGAS activation, whereas pharmacological inhibition with a potent human cGAS inhibitor reduced phosphorylated TDP-43, restored lysosomal and phagocytic programs, normalized microglial reactivity, and reversed TDP-43-associated RNA splicing defects. In vivo, cGAS inhibition in TDP-43 Q331K mice reversed widespread RNA splicing abnormalities across neurons and oligodendrocyte lineage cells, attenuated neurodegenerative pathology, and preserved motor function. Together, these findings identify cGAS as a druggable upstream regulator linking innate immune signaling to TDP-43-dependent RNA mis-splicing and neurodegeneration, and establish cGAS inhibition as a promising therapeutic strategy for ALS.

DOI: https://doi.org/10.64898/2026.02.24.707791
J Clin Transl Hepatol. 2026 Feb 28. 14(2): 121-136

Bidirectional Regulation between Metabolic Dysfunction-associated Steatotic Liver Disease and Sarcopenia via Liver-muscle Crosstalk.

Yeyu Song, Yameng Liu, Jie Jiang, Youjie Zheng, Zixuan Wang, Cen Xie, Jian-Gao Fan.

   Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) and sarcopenia frequently coexist, yet their causal relationship and underlying mechanisms remain poorly defined. This study aimed to investigate whether a bidirectional causal link exists between MASLD and sarcopenia and to identify the molecular mediators involved in liver-muscle crosstalk.
Methods: We applied Mendelian randomization to test the causal effect of sarcopenia-related traits on MASLD risk. To capture distinct clinical features, we established complementary mouse models, including diet-induced and genetic (ob/ob) MASLD models, a stelic animal model, and a drug-induced muscle atrophy model. Multi-tissue transcriptomic profiling was performed on liver and muscle to uncover altered pathways.
Results: Complementing prior genetic evidence establishing MASLD as a causal factor for sarcopenia, our Mendelian randomization analysis revealed that diminished muscle mass and muscle function contribute to an elevated risk of MASLD. In mice with MASLD, we observed loss of muscle mass, reduced strength, and ectopic lipid deposition in skeletal muscle. Conversely, muscle atrophy exacerbated hepatic steatosis, inflammation, and fibrosis in MASLD mice. Transcriptional profiling revealed that sarcopenia impairs hepatic metabolic homeostasis by enhancing fatty acid uptake and impairing oxidative phosphorylation, while MASLD, in turn, promotes muscle dysfunction by exacerbating inflammatory responses and metabolic dysfunction. We further identified C-C motif chemokine ligand 2 as a key myokine that drives MASLD, and adrenomedullin as a key hepatokine that triggers sarcopenia.
Conclusions: Our findings suggest a potential bidirectional causal relationship between MASLD and sarcopenia, which may be partially mediated by C-C motif chemokine ligand 2 and adrenomedullin.

Keywords:  Adrenomedullin; C-C motif chemokine ligand 2; Liver-muscle crosstalk; Mendelian randomization; Metabolic dysfunction-associated steatotic liver disease; Sarcopenia

DOI:  https://doi.org/10.14218/JCTH.2025.00538
Cell Rep. 2026 Mar 06. pii: S2211-1247(26)00104-X. [Epub ahead of print]45(3): 117026

ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.

Heegwon Shin, Tyler J Dorrity, Justin Aruda, Kenenni A Wiegand, Jung Seung Nam, Jiping Yang, Aidan S Jones, Jake A Gertie, Meera K Singh, Yuanjun Yin, Keer He, Rafan Sarker, Rajesh K Soni, Yousin Suh, Iok In Christine Chio, Silvi Rouskin, Hachung Chung.

  Endogenous (self) double-stranded RNAs (dsRNAs) in human cells can activate innate immune responses. ADAR1, an A-to-I editing enzyme of dsRNAs, suppresses aberrant immune activation by self-dsRNAs. However, how ADAR1 influences the cellular dsRNA landscape remains unclear. We show that human ADAR1 downregulates self-dsRNA abundance through editing-dependent and editing-independent mechanisms. We further conducted quantitative dsRNA sequencing on wild-type and ADAR1-deficient cells. dsRNAs are enriched in protein-coding mRNAs-especially those with repetitive elements and elongated 3' UTRs-and mitochondrial RNAs. ADAR1-regulated dsRNA transcripts consist of nuclear-encoded mRNAs and, unexpectedly, mitochondria-encoded RNAs rarely edited by ADAR1. Accordingly, dsRNAs accumulate to high levels within the mitochondria of ADAR1-deficient cells. Mass spectrometry and biochemical assays can detect ADAR1p150 in mitochondrial fractions. Notably, ADAR1 loss sensitizes cells to inflammation under mitochondrial stress (e.g., herniation and X-ray irradiation). Hence, we show that dsRNAs regulated by ADAR1 go beyond A-to-I edited transcripts and that ADAR1 can control mitochondrial dsRNAs.

Keywords:  A-to-I editing; ADAR1; AGS; Aicardi-Goutieres syndrome; CP: immunology; CP: molecular biology; IFN; PKR; double-stranded RNA; dsRNA; dsRNA-seq; innate immunity; mitochondria; mitochondrial stress; protein kinase R; type 1 interferon

DOI:  https://doi.org/10.1016/j.celrep.2026.117026
Aging Cell. 2026 Mar;25(3): e70441

Aged Male Mice Remain Glucose Tolerant Despite Increased Energy Storage Efficiency Favoring Diet-Induced Obesity.

Liz Gray, Kaylynn Vidmar, Marita Rivir, Vishnupriya J Borra, Diego Perez-Tilve.

Obesity and aging are converging health challenges, contributing to morbidity in older populations. However, the specific contribution of age to susceptibility to obesity is unclear. This study examined the impact of age on susceptibility to diet-induced obesity (DIO) and calorie restriction (CR) in male mice. Young (2-3 months) and old (17-24 months) lean C57BL/6J male mice were fed a standard chow diet (CD) or a high-fat diet (HFD) for 28 days, then underwent 18 days of CR. We monitored body weight, body composition, energy intake and expenditure, glucose tolerance, and gene expression in metabolically relevant tissues. HFD-fed old mice exhibited more fat mass gain but, surprisingly, protection from glucose intolerance. In comparison, young controls exhibited resistance to DIO due to reduced calorie storage efficiency. Gene expression analysis suggested reduced plasticity and lipid turnover in visceral adipose tissue but increased subcutaneous adipose tissue plasticity in old mice. The increased energy storage did not protect old mice from body weight loss following CR. Old mice exhibit increased susceptibility to DIO due to near optimal efficiency storing calories as fat. This susceptibility correlates with increased energy storage efficiency and the absence of energy demanding anabolic processes, like lean mass accrual, exhibited by young mice. Despite increased predisposition to obesity, lifelong leanness confers resilient glycemic control to old mice, emphasizing the importance of maintaining a healthy body weight and dietary habits throughout life to mitigate age-related metabolic risks.

DOI: https://doi.org/10.1111/acel.70441
Biochem Pharmacol. 2026 Mar 08. pii: S0006-2952(26)00211-X. [Epub ahead of print]249 117879

Ginkgetin alleviates cisplatin-induced muscle atrophy via inhibition of the macrophage cGAS-STING pathway.

Xiaojing Chen, Jianwei Lin, Jingchun Lv, Liya Wen, Qi Wang, Dapeng Jiang.

  Chemotherapy-induced muscle atrophy is a severe side effect, impairing patients' quality of life and overall survival. However, the persistence of muscle atrophy in cancer survivors long after treatment completion suggests that it is driven not only by the agent's direct toxicity, but also by a persistent, chemotherapy-induced pathological immune microenvironment. Elucidating the interplay between chemotherapy drugs, the immune microenvironment, and muscle cells is essential for identifying mechanisms and potential therapeutic targets. In this study, we investigated the critical role of macrophages in potentiating cisplatin-induced muscle atrophy by identifying a novel "amplification effect". Specifically, conditioned medium from cisplatin-activated macrophages synergized with cisplatin to induce severe myotube atrophy. We identify that cisplatin activates the cGAS-STING pathway in macrophages by inducing cytosolic DNA leakage, which drives their M1 polarization and pro-inflammatory cytokines release. The pro-inflammatory microenvironment amplifies the myotoxicity of cisplatin and promotes severe muscle atrophy. Notably, ginkgetin reverses the cisplatin-induced inflammatory microenvironment by binding to the STING protein within macrophage. The mechanism of the cisplatin-macrophage-muscle cell axis was also validated in an in vivo mouse model of cisplatin-induced muscle atrophy. Furthermore, we discovered that multiple chemotherapeutic agents could promote macrophages to polarize towards the M1 phenotype and release various inflammatory factors. These findings suggest that the macrophage cGAS-STING pathway is a key common mechanism and a broad-spectrum therapeutic target for treating chemotherapy-induced muscle atrophy. Collectively, this study elucidates the critical role of macrophage-mediated microenvironment in cisplatin-induced muscle atrophy, thereby providing a promising therapeutic target for chemotherapy-induced muscle atrophy.

Keywords:  Cisplatin; Ginkgetin; Macrophage; Muscle Atrophy; cGAS-STING Pathway

DOI:  https://doi.org/10.1016/j.bcp.2026.117879