bims-musmir 2026-02-01 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–02–01
nineteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.
Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
Cellular survivorship bias as a mechanistic driver of muscle stem cell aging.
Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
ATH-1105 mitigates multiple pathologies in ALS models both alone and in combination with riluzole.
Distinct Argonaute2-associated small RNA profiles in microglia and neurons drive cell-specific responses in a mouse model of temporal lobe epilepsy.
Spatiotemporally regulated mitochondrial genome editing via enzyme and NIR-activated CRISPR/Cas9 nanoplatform.
Deciphering the Regulatory Landscape of mRNA-miRNA-lncRNA Interactions in COVID-19 Severity: Insights from Transcriptomic Analysis.
RIG-I Mediated Neuron-Specific IFN Type 1 Signaling in FUS-ALS Induces Neurodegeneration and Offers New Biomarker-Driven Individualized Treatment Options for (FUS-)ALS.
Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.
Apolipoprotein A1 reduces blood-spinal cord barrier leakage, improves astrocytic coverage, and enhances motor neuron survival to restore the neurovascular unit in ALS mice.
Identifying Susceptibility Genes and Shared Genetic Architecture for Longevity and Muscle Weakness.
Peptide OH-CATH30 Mitigates Cachexia-Induced Muscle Atrophy via Modulation of TLR4-Associated Inflammation.
Modulation of the miR-485-3p/PGC-1α Pathway by ASO-Loaded Nanoparticles Attenuates ALS Pathogenesis.
G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.
The gut microbiome and dietary interventions in cancer cachexia.
Role of lysosomal morphology in aging and age-related diseases.
Enhanced lysosomal exocytosis and altered growth factor signaling are associated with cartilage pathology in a zebrafish model of MPSIVA.
Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.

JCI Insight. 2026 Jan 27. pii: e200396. [Epub ahead of print]

Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.

Bowen Xu, Aniket S Joshi, Meiricris Tomaz da Silva, Silin Liu, Ashok Kumar.

  Cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting, commonly affecting cancer patients, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrated that KPC tumor growth induced myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhanced the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbated muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered new intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Together, our study revealed previously unrecognized molecular mechanisms that regulates skeletal muscle homeostasis and identified potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.

Keywords:  Cancer; Cell biology; Expression profiling; Muscle; Muscle biology

DOI:  https://doi.org/10.1172/jci.insight.200396
Autophagy. 2026 Jan 28.

Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.

Fasih A Rahman, Mackenzie Q Graham, Joe Quadrilatero.

  Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.

Keywords:  Fibers; metabolism; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2026.2623988
Science. 2026 Jan 29. 391(6784): 517-521

Cellular survivorship bias as a mechanistic driver of muscle stem cell aging.

Jengmin Kang, Daniel I Benjamin, Qiqi Guo, Chauncey Evangelista, Soochi Kim, Marina Arjona, Pieter Both, Mingyu Chung, Ananya K Krishnan, Gurkamal Dhaliwal, Richard Lam, Thomas A Rando.

Aging is characterized by a decline in the ability of tissue repair and regeneration after injury. In skeletal muscle, this decline is largely driven by impaired function of muscle stem cells (MuSCs) to efficiently contribute to muscle regeneration. We uncovered a cause of this aging-associated dysfunction: a cellular survivorship bias that prioritizes stem cell persistence at the expense of functionality. With age, MuSCs increased expression of a tumor suppressor, N-myc down-regulated gene 1 (NDRG1), which, by suppressing the mammalian target of rapamycin (mTOR) pathway, increased their long-term survival potential but at the cost of their ability to promptly activate and contribute to muscle regeneration. This delayed muscle regeneration with age may result from a trade-off that favors long-term stem cell survival over immediate regenerative capacity.

DOI: https://doi.org/10.1126/science.ads9175
Elife. 2026 Jan 26. pii: RP95576. [Epub ahead of print]13

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.

Kanako Shinno, Yuri Miura, Koichi M Iijima, Emiko Suzuki, Kanae Ando.

  Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.

Keywords:  D. melanogaster; aging; autophagy; cell biology; mitochondria; neuronal proteostasis; protein aggregation; proteome

DOI:  https://doi.org/10.7554/eLife.95576
Front Neurol. 2025 ;16 1582765

ATH-1105 mitigates multiple pathologies in ALS models both alone and in combination with riluzole.

Andrée-Anne Berthiaume, Kayla N Kleist, Sherif M Reda, Sharay E Setti, Wei Wu, Jewel L Johnston, Robert W Taylor, Liana R Stein, Kevin J Church.

   Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration, muscle atrophy, and paralysis. The complexity of ALS pathology, driven by factors such as TDP-43 pathology, excitotoxicity, and neuroinflammation, has hindered therapeutic development. While riluzole (an anti-excitotoxic agent) is the current standard treatment, additional therapeutics are needed to address the broad spectrum of ALS-related pathology. ATH-1105, a small-molecule positive modulator of hepatocyte growth factor (HGF) signaling, has shown promise in preclinical models of ALS. Given the multifactorial nature of ALS and the growing recognition that combination approaches may represent the best treatment options, we investigated the therapeutic potential of ATH-1105 in a TDP-43-driven mouse model of ALS, by comparing and combining it with the known efficacious treatment of riluzole. Additionally, we characterize the mechanism by which ATH-1105 induces neuroprotective effects, emphasizing its effects on TDP-43 pathology.
Methods: In vivo, the impact of daily oral treatment with ATH-1105, alone and in combination with riluzole, was evaluated in Prp-TDP43A315T hemizygous transgenic ALS mice. In vitro, the impact of ATH-1105 on TDP-43-related pathology was assessed in rat primary spinal motor neurons subjected to glutamate toxicity. To demonstrate target engagement, the neuroprotective effects of ATH-1105 were assessed via siRNA-mediated knockdown of MET (HGF receptor).
Results: In vivo, ATH-1105 significantly improved neuromuscular function and reduced body weight loss, neurodegeneration, inflammation, and TDP-43 phosphorylation. The combination of ATH-1105 with riluzole led to greater therapeutic effects than either treatment alone. In vitro, the neuroprotective effects of ATH-1105 were shown to be associated with MET activation in motor neurons, which was confirmed via siRNA-mediated knockdown of MET. In motor neurons subjected to glutamate toxicity, ATH-1105 reduced extranuclear and phosphorylated TDP-43, and increased GSK3β phosphorylation (inactivation), a kinase involved in TDP-43 pathology. Additionally, ATH-1105 reduced the abnormal increase in autophagic proteins following glutamate toxicity.
Discussion: Our study underscores the therapeutic potential of ATH-1105 in treating ALS, both as a standalone treatment and in combination with riluzole. ATH-1105 demonstrates neuroprotective effects that slow neuromuscular deterioration in a relevant mouse model, aligning with the need to counteract the neurodegeneration central to ALS.

Keywords:  ALS; TDP-43; hepatocyte growth factor; neurofilament light chain; neuroprotection; neurotrophic factor; riluzole; small-molecule therapeutics

DOI:  https://doi.org/10.3389/fneur.2025.1582765
Neurobiol Dis. 2026 Jan 22. pii: S0969-9961(26)00028-8. [Epub ahead of print]220 107284

Distinct Argonaute2-associated small RNA profiles in microglia and neurons drive cell-specific responses in a mouse model of temporal lobe epilepsy.

Leticia Villalba-Benito, Justine Mathoux, Theresa Auer, Kaushik Narasimhan, Ruth Colbert, James P Reynolds, Elizabeth Brindley, Aasia Batool, Thomas D M Hill, Mairead Diviney, Morten T VenØ, Marco Prinz, Niamh M C Connolly, Dearbhaile Dooley, David C Henshall, Gary P Brennan.

  Small RNAs including microRNAs (miRNAs) and tRNA fragments (tRFs) are key post-transcriptional regulators of gene expression in temporal lobe epilepsy (TLE), but the cellular origin of these changes is often unclear. Here, we dissected the cell-type specific small RNA landscape, focussing on miRNA and tRFs, during epileptogenesis and in chronic epilepsy by profiling the RNA-induced silencing complex (RISC) using novel, transgenic mice with inducible expression of a FLAG-tagged Argonaute 2 protein driven specifically in neurons (Thy1-Ago2) or microglia (Cx3cr1-Ago2). We induced epilepsy in male mice via intra-amygdala microinjection of kainic acid and tracked miRNA expression over time in the hippocampus. Microglia and neurons displayed distinct and largely non-overlapping small RNA profiles across disease. Shortly following the epileptogenic insult, we detected a rapid microglial miRNA and tRF response which was sustained in chronic stages of the disease whereas small RNA changes in neurons displayed a delayed but sustained wave of unique changes as the disease progressed. Interestingly, our data reveals selective loading and incorporation of miRNAs into Ago2/RISC complexes, independent of overall abundance, in a cell- and disease-stage specific manner as well as differential processing of tRNAs in microglia compared to neurons. Additionally we found that certain epilepsy-associated miRNAs, previously considered ubiquitous, display dysregulation in multiple cell types while exhibiting cell-specific activity. Together our results demonstrate the cell-specific small RNA responses and functions to epileptogenic insults and shed further light on the complexity of post-transcriptional gene dysregulation in TLE. The findings indicate the potential advantages of targeted, cell-specific therapeutic strategies to effectively modulate miRNA pathways in epilepsy.

Keywords:  Argonaute2; Epileptogenesis; Microglia; Temporal lobe epilepsy; microRNA

DOI:  https://doi.org/10.1016/j.nbd.2026.107284
Chem Sci. 2026 Jan 13.

Spatiotemporally regulated mitochondrial genome editing via enzyme and NIR-activated CRISPR/Cas9 nanoplatform.

Fei Yang, Qianqin Ran, Jiahui Chen, Guochen Bao, Yuezhong Xian, Cuiling Zhang.

Mitochondrial DNA (mtDNA) mutations play critical roles in tumor progression and metabolic reprogramming. Controllable gene editing within tumor cell mitochondria remains a challenge due to the double-membrane barrier and the lack of tumor-selective activation. Herein, we report a dual-responsive CRISPR/Cas delivery platform (UCRP-TPP) that enables spatiotemporally regulated mtDNA editing for targeted tumor therapy. This nanoplatform integrates near infrared light-responsive upconversion nanoparticle (UCNP), an apurinic endonuclease 1 (APE-1)-responsive DNA complex, and a mitochondrial-targeting ligand (TPP), ensuring selective activation and mitochondrial release of Cas9/sgRNA complexes. Upon activation by endogenous APE-1 enzyme and exogenous NIR light, UCRP-TPP induces mtDNA editing by CRISPR/Cas, which leads to mtDNA copy number reduction, mitochondrial membrane depolarization, reactive oxygen species generation, and tumor cell apoptosis. In vivo studies further confirm the robust antitumor efficacy of the UCRP-TPP-based nanoplatform. This work presents a versatile and controllable mitochondrial gene-editing strategy.

DOI: https://doi.org/10.1039/d5sc07976d
Recent Pat Biotechnol. 2026 Jan 20.

Deciphering the Regulatory Landscape of mRNA-miRNA-lncRNA Interactions in COVID-19 Severity: Insights from Transcriptomic Analysis.

Soudabeh Sabetian, Mahboubeh Sadeghi, Ehsan Saleh Ahmadi, Claudia Cava, Mahintaj Dara, Mohammad Hossein Morowvat.

   BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has a highly variable clinical course, ranging from mild symptoms to severe systemic complications. Understanding the molecular basis of disease severity is essential for improving diagnostic and therapeutic strategies.
OBJECTIVE: In this study, we performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from patients with mild and severe COVID-19 to identify differentially expressed mRNAs and long noncoding RNAs (lncRNAs), and to construct a regulatory network including microRNAs (miRNAs).
METHODS: Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from patients with mild and severe COVID-19 was performed to identify differentially expressed mRNAs and long noncoding RNAs (lncRNAs), and to construct a regulatory network including microRNAs (miRNAs) using Cytoscape.
RESULTS: A total of 674 mRNAs and 215 lncRNAs were differentially expressed between severe and mild cases, with key pathways enriched in cytokine-cytokine receptor interaction and immunological synapse signaling. The lncRNAs NEAT1 and MALAT1 were identified as regulatory hubs and were broadly expressed across multiple immune and organ tissues. Predicted miRNAs (experimentally supported in interaction databases) were associated with inflammation- and cancer-related signaling pathways, including PI3K-Akt, JAK/STAT, and TNF.
DISCUSSION: Our findings are consistent with recent patents (e.g., US2022/0298584A1, EP3892280A3, WO2023147669A1) that propose the use of noncoding RNAs and cytokines as biomarkers for COVID-19 diagnosis and severity assessment.
CONCLUSION: Our findings are consistent with recent patents (e.g., "US20220298584A1", "EP3892280A3", "WO2023147669A1") that propose the use of noncoding RNAs and cytokines as biomarkers for COVID-19 diagnosis and severity assessment. This integrative transcriptomic analysis highlights the regulatory role of noncoding RNAs in COVID-19 progression, exemplified by the central hub lncRNAs NEAT1 and MALAT1, which interact with inflammation- associated miRNAs and mRNA targets to modulate cytokine signaling. These findings offer specific transcriptomic biomarkers with potential for clinical application and therapeutic targeting.

Keywords:  COVID-19; Gene expression; Regulatory network.; lncRNA; miRNA

DOI:  https://doi.org/10.2174/0118722083418291251127062436
Adv Sci (Weinh). 2026 Jan 28. e17135

RIG-I Mediated Neuron-Specific IFN Type 1 Signaling in FUS-ALS Induces Neurodegeneration and Offers New Biomarker-Driven Individualized Treatment Options for (FUS-)ALS.

Marcel Naumann, Theresa M Wierschin, Stefanie Kretschmer, Banaja P Dash, Aaron Held, Andrea Salzinger, Kevin Peikert, Anže Karlek, Hannes Glaß, Dajana Großmann, René Günther, Susanne Petri, Annekathrin Rödiger, David Brenner, Francisco Pan-Montojo, Eleonora Aronica, Markus Kipp, Vitaly Zimyanin, Jared Sterneckert, Torsten Grehl, Noah D Seebacher, Tobias M Böckers, Alberto Catanese, Brian J Wainger, Patrick Oeckl, Min Ae Lee-Kirsch, Andreas Hermann.

  Recent research demonstrated activation of the innate immune system in ALS models. This pathway can be activated by cGAS-STING sensing of cytosolic DNA that accumulates as a result of chronic DNA damage and defective mitochondria, both of which was identified as pathology in FUS-ALS. Therefore, we analyzed innate immune pathways in FUS-ALS, which revealed upregulation of interferon-stimulated genes (ISGs) and activation of the TBK1-IRF3 pathway in FUSmut iPSC-derived spinal motor neurons (sMNs). Accumulation of cytosolic dsRNA and its sensor RIG-I, but not MDA5, was found to be significantly upregulated in FUSmut sMNs, which was abolished upon siRNA-mediated knockdown of RIG-I. RIG-I was highly expressed in FUS-ALS post-mortem α-MNs. IFN treatment of FUSwt sMNs phenocopied the axonal degeneration of FUSmut sMNs. Mitochondrial transcription, a known source of dsRNA, was found to be upregulated in compartmental axonal RNAseq analysis and its inhibition reduced ISGs in FUS-ALS sMNs. The JAK-STAT inhibitor ruxolitinib alleviated the upregulated ISG expression and reversed the axonal degeneration of sMNs. Finally, we analyzed ISG expression in peripheral blood from 18 FUS-ALS patients, eight of whom had a significantly elevated interferon signature. RIG-I-mediated innate immune activation in sMNs may be an interesting novel individualized biomarker-driven therapeutic target in (FUS-) ALS. A one-sentence summary of your paper: RIG-I-mediated innate immune activation is found in FUS-ALS spinal motor neurons caused by cytosolic dsRNA accumulation due to mitochondrial transcriptional activation and is amenable to JAK-STAT inhibition and might thus be an interesting novel individualized biomarker-driven therapeutic approach in (FUS-) ALS.

Keywords:  RIG‐I; RIG‐I like receptors; RNA‐sequencing; cGAS‐STING pathway; double‐stranded RNA; pathogen‐associated molecular patterns; type 1 interferon

DOI:  https://doi.org/10.1002/advs.202417135
Geroscience. 2026 Jan 28.

Coenzyme Q10 supplementation raises plasma levels without improving mitochondrial function in older adults.

Malte Schmücker, Cathrine Tranberg, Jacob Borch, Mette Killerup Kaae, Michelle Damgaard, Mathias Flensted-Jensen, Ida Blom, Marco Morosetti, Sara Barbarossa, Patrick Orlando, Luca Tiano, Flemming Dela, Jørn Wulff Helge, Steen Larsen.

  Mitochondrial function is important to healthy aging, as it influences energy metabolism, oxidative stress, and physical performance. With age, mitochondrial function and biosynthesis of coenzyme Q10 (CoQ10) may change. CoQ10 serves as a key antioxidant and component of the electron transport system. Supplementation with CoQ10 may help preserve mitochondrial function and support healthy aging. Forty older community-dwelling adults (74 ± 4 years) received either daily oral CoQ10 supplementation (400 mg daily) or a placebo in a 12-week double-blinded, randomized, placebo-controlled design. Before and after the supplementation period, muscle biopsies were obtained. Subsequently, oral glucose tolerance tests (OGTT) and VO2max tests were conducted. Mitochondrial respiratory capacity (MRC), mitochondrial H2O2 emission, and mitochondrial content were assessed in both isolated mitochondria and permeabilized muscle fibers. Levels and redox status of CoQ10 were measured in plasma, muscle tissue, and isolated skeletal muscle mitochondria. Additionally, resting metabolic rate, cognitive function, and body composition were investigated. Plasma levels of CoQ10 increased significantly without changes in redox status after the intervention. No changes between groups or time were observed in muscle and isolated mitochondria regarding MRC, H2O2 emission, mitochondrial content, and levels of CoQ10. Glucose homeostasis, VO2max, and body composition were also unchanged. Twelve weeks of supplementation led to increased plasma levels of CoQ10, with unchanged levels in muscle tissue and isolated mitochondria. No differences in mitochondrial function, glucose homeostasis, and physical performance were found in a cohort of robust older adults.

Keywords:  Antioxidant; Healthy aging; Mitochondrial function; Reactive oxygen species

DOI:  https://doi.org/10.1007/s11357-025-02068-9
Front Aging Neurosci. 2025 ;17 1684694

Apolipoprotein A1 reduces blood-spinal cord barrier leakage, improves astrocytic coverage, and enhances motor neuron survival to restore the neurovascular unit in ALS mice.

Svitlana Garbuzova-Davis, Larai Manora, Cesario V Borlongan.

   Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive, age-related motor neuron degenerative disease with multiple causal factors. Dyslipidemia has been identified as an important pathological element. Impaired lipid protein metabolism manifests in ALS patients and in an ALS mouse model. Apolipoprotein components are the primary regulators of plasma lipid metabolism. Apolipoprotein A1 (ApoA1), a high-density lipoprotein, acts as an antioxidant and reduces inflammation, preventing blood vessel injury. However, the effects of ApoA1 upon the ALS-damaged endothelium in the CNS are unknown. The objective of the study was to determine the effect(s) of injecting ApoA1 into G93A SOD1 mice at the early symptomatic stage.
Methods: A single dose of ApoA1 or media was systemically administered into 13-week-old G93A SOD1 male and female mice. Body weight and tests of motor function were evaluated weekly for 4 weeks post-injection. Permeability of spinal cord capillaries was determined by Evans blue (EB) fluorescent dye injected into mice at 17 weeks of age. Immunohistochemical analyses determined the statuses of glial cells and ApoA1 distributions in ALS mice cervical/lumbar spinal cords. Motor neurons in cervical/lumbar spinal cord ventral horns of ApoA1-treated and media-injected ALS mice were stained with cresyl violet for histological analyses.
Results: ApoA1 injected into G93A SOD1 mice at the early symptomatic stage significantly benefited both male and female animals by (1) delaying behavioral disease progression; (2) reducing EB capillary leakage into spinal cord parenchyma; (3) lessening astrogliosis and microgliosis; (4) protein incorporation into capillary endothelium and motor neurons; and (5) improving survival of motor neurons in the spinal cord.
Conclusion: Our novel data showed that systemically administered ApoA1 benefited ALS mice of both sexes, likely by beneficial effects on damaged microvessels, possibly engendering restoration of neurovascular unit integrity. Moreover, an anti-inflammatory ApoA1 effect was demonstrated by the reduction of glial cell activation, potentially mitigating vascular injury. The results of our preclinical study suggest that ApoA1 may be a potential protein-mediated therapeutic for restoring vascular function. Our novel strategy may lead to future clinical trials, furthering our goal of effectively treating ALS patients.

Keywords:  ALS; G93A SOD1 mutant mice; apolipoprotein A1; astrocytes; behavior; blood–spinal cord barrier permeability; microglia; mouse sex

DOI:  https://doi.org/10.3389/fnagi.2025.1684694
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70197

Identifying Susceptibility Genes and Shared Genetic Architecture for Longevity and Muscle Weakness.

Yilong Lin, Yun Zhang, Shengjie Lin, Songsong Wang, Zhiqiang Que, Yue Zhang, Jing She, Ruidan Zhao, Jiawei Chen, Anqi Qiu, Shinan Wu, Ruiqin Yang, Liyi Zhang, Qingmo Yang.

   BACKGROUND: Longevity and muscle strength are heritable traits, and age-related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanisms underlying lifespan and sarcopenia remain unclear. This study aimed to identify genes associated with longevity and muscle weakness and to characterize their shared genetic architecture.
METHODS: We integrated the largest genome-wide association studies (GWAS) on longevity (age > 90th: n = 11 262 cases; age > 99th: n = 3484 cases) and muscle weakness (European Working Group on Sarcopenia in Older People (EWGSOP): n = 48 596 cases; Foundation for the National Institutes of Health (FNIH): n = 20 335 cases) with Genotype-Tissue Expression (GTEx) v8 multi-tissue expression quantitative trait locus (eQTL) data. Gene-trait associations were evaluated using multi-tissue and single-tissue TWAS, and validated using Multi-marker Analysis of GenoMic Annotation (MAGMA). Mendelian randomization (MR) and colocalization were applied to test causality and shared variants. Cross-trait genetic correlation was estimated with LDSC, and pleiotropic loci were identified by pleiotropy analysis under the composite null hypothesis (PLACO) followed by Functional Mapping and Annotation (FUMA)/MAGMA annotation.
RESULTS: Across TWAS approaches, APOC1 and TOMM40 were identified as longevity-associated genes, while DYM and TGFA were susceptibility genes for muscle weakness. In MR analysis, higher expression of APOC1 and TOMM40 increased the odds of longevity (OR > 1, p < 0.05), whereas higher expression of DYM and TGFA reduced the risk of muscle weakness (OR < 1, p < 0.05). Colocalization supported shared causal variants for APOC1 (rs429358, PP.H4 = 0.81) and TOMM40 (rs429358, PP.H4 = 0.85) with longevity (age > 90th survival percentile), and for DYM and TGFA with muscle weakness defined by both EWGSOP and FNIH (PP.H4 > 0.80). A significant negative genetic correlation was observed between longevity and muscle weakness (Rg < 0, p < 0.05). Cross-trait pleiotropy analysis identified several pleiotropic genes (PVRL2, PPP1R9A, SLC39A8 and the TOMM40/APOE/APOC1 gene cluster) that influence both longevity and muscle weakness.
CONCLUSIONS: We identified susceptibility genes for longevity (APOC1, TOMM40) and muscle weakness (DYM, TGFA) and uncovered shared pleiotropic loci linking aging and muscle decline. These findings improve the understanding of the genetic architecture underlying aging-related phenotypes and provide potential molecular targets for promoting healthy aging and reducing late-life disability.

Keywords:  genome‐wide cross‐trait analysis; longevity; muscle weakness; sarcopenia; shared genetic architecture; transcriptome‐wide association studies

DOI:  https://doi.org/10.1002/jcsm.70197
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70195

Peptide OH-CATH30 Mitigates Cachexia-Induced Muscle Atrophy via Modulation of TLR4-Associated Inflammation.

Qiquan Wang, Jian Li, Mengqi Yang, Caifen Guo, Ming Zhang, Chunping Huang, Xiang Wang, Dongqin Zhang, Lin Zeng, Hao Ke, Yunling Wen, Shengan Li, Wenhui Lee, Limin Zhao, Xinqiang Lan, Yang Xiang.

   BACKGROUND: Cachexia, characterized by severe weight loss and muscle atrophy, frequently occurs in chronic conditions such as sepsis, cancer and chemotherapy, with limited effective treatments. Despite similar clinical manifestations, the underlying mechanisms across different disease contexts remain unclear. Identifying common pathways could lead to novel therapies. This study examines the role of Toll-like receptor 4 (TLR4), which is upregulated in various cachexia models, and assesses the therapeutic potential of the TLR4-inhibiting peptide OH-CATH30 in mitigating muscle atrophy.
METHODS: In vivo models using 8-week-old mice treated with lipopolysaccharide (LPS), 4T1 tumour cells and cisplatin were used to investigate common pathways in cachexia. In vitro models were established by treating C2C12 myotubes with TNF-α, 4T1 culture supernatants and cisplatin. OH-CATH30's effects on muscle atrophy were assessed by measuring myotube diameter, grip strength, muscle weight and muscle fibre cross-sectional area (CSA) via H&E staining. RNA-seq, qPCR, ELISA and Western blotting were performed to explore pathways in cachexia-induced muscle atrophy and OH-CATH30's action mechanism.
RESULTS: Transcriptomic analysis showed significant enrichment of inflammation and protein degradation pathways in skeletal muscle in LPS-induced sepsis, 4T1 tumour-induced cancer cachexia and cisplatin-induced cachexia models, with upregulated expression of TLR4 pathway genes such as Cd14, Tlr4 and Irak4 (p < 0.05). In myotube atrophy models induced by TNF-α, 4T1 and cisplatin, OH-CATH30 significantly increased MyHC protein levels (p < 0.05) and myotube diameter (p < 0.05). In mouse cachexia models induced by LPS, 4T1 and cisplatin, OH-CATH30 treatment significantly increased body weight (p < 0.05), muscle weight (p < 0.001), CSA (p < 0.05) and improved grip strength (p < 0.05). Transcriptomic analysis further revealed that OH-CATH30 treatment downregulated expression of inflammation and protein degradation-related genes across all cachexia models. In 4T1-treated mice, qPCR confirmed OH-CATH30 reduced mRNA levels of Il6 (p = 0.05), Mstn (p < 0.0001) and protein degradation genes such as Trim63, Fbxo32, Bnip3, Gabarapl1 and Ulk1 (p < 0.05). ELISA showed reduced serum IL-6 levels, and Western blot confirmed downregulation of atrogin1 (p < 0.05) and autophagy marker LC3II (p < 0.05) with OH-CATH30 treatment. Pharmacological inhibition of TLR4 using TAK-242 recapitulated the protective effects of OH-CATH30, with no additive benefit observed (p > 0.05).
CONCLUSIONS: Our findings underscore the critical role of TLR4 signalling in cachexia-associated muscle wasting across different disease contexts and demonstrate the efficacy of OH-CATH30, a TLR4 inhibitor, in alleviating muscle atrophy in various cachexia models.

Keywords:  OH‐CATCH30; TLR4; cachexia; inflammation; muscle atrophy; protein degradation

DOI:  https://doi.org/10.1002/jcsm.70195
Int J Mol Sci. 2026 Jan 07. pii: 615. [Epub ahead of print]27(2):

Modulation of the miR-485-3p/PGC-1α Pathway by ASO-Loaded Nanoparticles Attenuates ALS Pathogenesis.

In Soo Ryu, Dae-In Ha, Yeon-Joo Jung, Hyo Jin Lee, Insun Kim, Yu Na Lim, Hyun Su Min, Seung Hyun Kim, Ilsang Yoon, Hyun-Jeong Cho, Jin-Hyeob Ryu.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial function and neuroprotection. We also evaluated the therapeutic potential of BMD-001S, a nanoparticle-based formulation encapsulating an antisense oligonucleotide targeting miR-485-3p. Our results demonstrated that miR-485-3p expression was significantly elevated in both SOD1G93A-expressing HMC3 microglial cells and in the spinal cords of SOD1G93A transgenic mice at late disease stages, implicating its contribution to ALS pathogenesis. Intravenous administration of BMD-001S effectively reduced miR-485-3p levels and restored PGC-1α mRNA and PGC-1α protein expression in the spinal cord. These molecular changes were associated with notable therapeutic outcomes, including reduced SOD1 protein aggregation, decreased neuroinflammation, and lower neurofilament light chain concentrations in cerebrospinal fluid. Moreover, BMD-001S treatment was associated with improvements in electrophysiological parameters and preservation of neuromuscular junction integrity during the observation period in SOD1G93A transgenic mice. Taken together, these findings suggest that miR-485-3p/PGC-1α pathway is a promising therapeutic target in ALS and support the potential of BMD-001S as a novel treatment strategy for the disease.

Keywords:  antisense nucleotide (ASO); microRNA; nanoparticle; neurodegenerative disease; neuroinflammation

DOI:  https://doi.org/10.3390/ijms27020615
Antioxidants (Basel). 2025 Dec 19. pii: 5. [Epub ahead of print]15(1):

G-Quadruplexes Abet Neuronal Burnout in ALS and FTD.

Alan Herbert.

  Expansion of d(GGGGC)n repeat in the C9ORF72 gene is causal for Amyotrophic Lateral Sclerosis (ALS) and Frontal Temporal Dementia (FTD). Proposed mechanisms include Repeat-Associated Non-AUG translation or the formation of G-quadruplexes (GQ) that disrupt translation, induce protein aggregation, sequester RNA processing factors, or alter RNA editing. Here, I show, using AlphaFold V3 (AF3) modeling, that the TAR DNA-binding protein (TDP-43) docks to a complex of GQ and hemin. TDP-43 methionines lie over hemin and likely squelch the generation of superoxide by the porphyrin-bound Fe. These TDP-43 methionines are frequently altered in ALS patients. Tau protein, a variant of which causes ALS, also binds to GQ and heme and positions methionines to detoxify peroxides. Full-length Tau, which is often considered prone to aggregation and a prion-like disease agent, can bind to an array composed of multiple GQs as a fully folded protein. In ALS and FTD, loss-of-function variants cause an uncompensated surplus of superoxide, which sparks neuronal cell death. In Alzheimer's Disease (AD) patients, GQ and heme complexes bound by β-amyloid 42 (Aβ4) are also likely to generate superoxides. Collectively, these neuropathologies have proven difficult to treat. The current synthesis provides a framework for designing future therapeutics.

Keywords:  ALS; Amyloid-beta; C9ORF72; FTD; G-quadruplex; TDP43; dementia; flipons; heme; oxidative stress

DOI:  https://doi.org/10.3390/antiox15010005
Curr Opin Clin Nutr Metab Care. 2026 Jan 29.

The gut microbiome and dietary interventions in cancer cachexia.

Rima Nasrah, R Thomas Jagoe.

   PURPOSE OF REVIEW: The gut microbiome (GM) is altered in cancer cachexia, and it is possible that such GM changes may promote or sustain features of cancer cachexia including changes in host metabolism and anorexia. As a result, there is growing interest in GM-focused interventions to address cancer cachexia. In this review, the factors that likely contribute to changes in GM in cancer cachexia are highlighted. Also, this review presents recent data on GM-derived predictive biomarkers for response to dietary interventions in cachexia.
RECENT FINDINGS: The importance of maintaining or increasing energy intake to combat cancer cachexia has become clearer in recent years. However, there is wide inter-individual variation in response to changes after dietary interventions. Two recent studies have reported GM features which predict response to different types of dietary interventions: enteral feeding in pancreatic cancer patients, and oral nutritional counselling promoting an energy and protein dense diet in a mixed cancer group attending a specialized cancer cachexia clinic. Each study reported that increased abundance of a specific GM taxon predicted a more favourable response to the dietary intervention used.
SUMMARY: GM features may prove to be important in identifying patients with cancer cachexia who are more or less likely to respond well to current dietary interventions. This has clear clinical implications and utility. Further studies will be needed to determine whether GM-targeted interventions can be developed to improve response to dietary interventions and the management of cachexia more generally.

Keywords:  cancer cachexia; diet; dietary interventions; gut microbiome; nutritional interventions

DOI:  https://doi.org/10.1097/MCO.0000000000001211
Ageing Res Rev. 2026 Jan 23. pii: S1568-1637(26)00025-5. [Epub ahead of print]115 103033

Role of lysosomal morphology in aging and age-related diseases.

Huimin Liu, Haiqing Tang, Shanshan Pang.

  Lysosomes are responsible for clearing cellular waste and facilitating material recycling, thus playing a crucial role in maintaining cellular homeostasis and even in resisting the development of various diseases. Lysosomes are highly dynamic organelles. While typically exhibiting a vesicular morphology, lysosomes can remodel into tubular structures under specific conditions; this morphological plasticity underpins their functional complexity. Aging triggers significant lysosomal morphological remodeling and functional decline, contributing to the development of age-related diseases, notably neurodegenerative disorders. Although lysosomal function has been extensively studied in age-related diseases, the mechanisms driving aging-associated morphological alterations and their pathophysiological significance remain elusive. This review synthesizes current knowledge on the regulation of lysosomal morphology and its changes and functions during aging and in age-related diseases. We propose that altered lysosomal morphology represents not merely a hallmark of aging, but also a significant determinant of lysosomal and cellular functions during aging. Targeting lysosomal morphology holds promise as an emerging strategy for counteracting functional deterioration in aged lysosomes and mitigating associated disease pathogenesis.

Keywords:  Aging; Lysosomes; Morphology; Tubulation; Vesicular enlargement

DOI:  https://doi.org/10.1016/j.arr.2026.103033
Dis Model Mech. 2026 Jan 26. pii: dmm.052582. [Epub ahead of print]

Enhanced lysosomal exocytosis and altered growth factor signaling are associated with cartilage pathology in a zebrafish model of MPSIVA.

Jen-Jie Lee, Po-Nien Lu, Lynn Dukes-Rimsky, Chelsi Jeter, Maxwell B Colonna, Andrzej B Poplawski, Gavin Arno, Jenna Hallman, Christina Underwood, Amrita Basu, Laura Pollard, Ryan J Weiss, Richard Steet, Heather Flanagan-Steet.

  Optimal lysosomal function is essential for early tissue development. This is evidenced by the large number of inherited disorders, collectively called the lysosomal storage disorders (LSDs), caused by lysosomal dysfunction. While it is clear that macromolecular accumulation adversely impacts tissue development, the breadth of downstream pathways contributing to pathology has yet to be elucidated. Multiple studies indicate mechanisms beyond lysosomal storage also profoundly influence early tissue formation. Of these, abnormal growth factor signaling has been linked to pathology in several different LSDs. Recent work in a zebrafish model of sialidosis demonstrated that mislocalizing lysosomal cathepsins by increased exocytosis disrupts the TGF-ß related signaling pathways that control skeletal formation. Here we show loss of the enzyme galns (N-acetyl galactosamine-6-sulfatase) also enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Unlike sialidosis, however, in galns mutants increased exocytosis was associated with reduced cathepsin activity, lower levels of TGFß and BMP signaling, and altered abundance of intra- and extracellular glycosaminoglycans. Together these data highlight a role for lysosomal exocytosis and protease-mediated alterations in growth factor signaling in onset of MPSIVA skeletal pathology.

Keywords:  Cartilage; Cathepsin; Exocytosis; Lysosomes; MPSIVA; Zebrafish

DOI:  https://doi.org/10.1242/dmm.052582
Redox Biol. 2026 Jan 16. pii: S2213-2317(26)00036-4. [Epub ahead of print]90 104038

Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.

Shadi Al-Mesitef, Daisuke Ando, Tomoya Saigasaki, Yuki Sakaguchi, Shunya Akagi, Abdulrahman Mousa, Sherif Rashad, Kuniyasu Niizuma.

  Transfer RNA-derived small RNAs (tDRs) are emerging regulators of cellular stress response, yet their biogenesis and activities during mitochondrial dysfunction remain poorly understood. Here we profiled tDRs generated in HEK293T cells exposed to inhibitors of respiratory complexes I-V (rotenone, TTFA, antimycin A, KCN, oligomycin) or to arsenite and assessed the impact of CRISPR-mediated angiogenin (ANG) knockout, ANG over-expression and recombinant ANG supplementation on the stress response and tDRs production. tDR-seq revealed stress-specific, highly ordered tDR repertoires: rotenone and antimycin predominantly induced internal (i-tRF) and 3' tRNA (tRF3) fragments, whereas arsenite induced anticodon-cleaved tRNA halves (tiRNAs). mito-tDRs were mostly internal fragments and antimycin induced the strongest mitochondrial tDRs expression. ANG deletion markedly impaired stress-induced tDR biogenesis and sensitized cells to antimycin and oligomycin stress, whereas its overexpression selectively enhanced tDR biogenesis and conferred protection against these mitochondrial stressor. Synthetic tDR mimics failed to rescue viability, implying that native modification patterns or cooperative tDR pools are required. tDR motif enrichment analysis identified YBX1-binding sites among antimycin-induced tDRs, and genetic perturbation of YBX1 phenocopied aspects of enhanced mitochondrial bioenergetics and stress resistance. Together, these findings demonstrate that context-specific, ANG-directed tDR biogenesis forms a crucial arm of the mitochondrial stress response.

Keywords:  Angiogenin; Mitochondrial stress; RNA binding proteins; YBX1; tRNA; tRNA derived fragments

DOI:  https://doi.org/10.1016/j.redox.2026.104038