bims-musmir 2026-06-21 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–06–21
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Short-changed: Limited short-chain fatty acid oxidative capacity in skeletal muscle mitochondria.
Myosin Post-Translational Modifications Associated With Critical Illness Myopathy.
Short-term high-fat feeding induces muscle-type-specific signaling adaptations in skeletal muscle of male rats.
Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle.
Critical illness impairs coordinated myogenesis: a prospective longitudinal study of skeletal muscle progenitor cell biology using serial muscle biopsies (SATELLITE study).
Administration of Pgk1 missense mutation leads to more effective mitigation of neurodegenerative effects observed in ALS mice and transgenic zebrafish.
The nucleus as a mechanobiological hub in muscle aging.
NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.
SARS-CoV-2-induced dysregulation in ADAR editing patterns persists post viral clearance in individuals with mild COVID-19.
Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP.
Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.
Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.

J Physiol. 2026 Jun 19.

Short-changed: Limited short-chain fatty acid oxidative capacity in skeletal muscle mitochondria.

Daniel G Sadler.



Keywords:  exercise; high‐fat diet; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/JP291630
Acta Physiol (Oxf). 2026 Jul;242(7): e70240

Myosin Post-Translational Modifications Associated With Critical Illness Myopathy.

Fernando Ribeiro, Bruno Di Geronimo, Nicola Cacciani, Anna Widgren, Yvette Hedström, Anselmo S Moriscot, Peter M Kasson, Shina C L Kamerlin, Jonas Bergquist, Lars Larsson.

   BACKGROUND: Critical illness myopathy is a common and devastating consequence of critical care, causing dramatic loss of muscle mass and function in intensive care unit patients. Functional deficits often exceed the loss in muscle mass and myosin content. However, the mechanisms underlying the loss of force and emergence of myosin-expressing non-force-generating fibers remain elusive.
METHODS: Myosin dysfunction was investigated in six intensive care unit patients exposed to a 12-day mechanical ventilation and immobilization period using mass spectrometry-based proteomics and molecular dynamics simulations.
RESULTS: Previous single muscle fiber analyses revealed decreased fiber size and specific force from the 1st to the 12th days in all patients. A subset of myosin-expressing fibers exhibiting a complete loss of contractile function was identified in three of the patients despite similar atrophy levels (~30%, p < 0.05) after 12 days. All fibers had decreased specific force after 12 days of mechanical ventilation, but 9% to 21% of the fibers were non-force generating. The decline in specific force was linked to 27 post-translational myosin modifications, including oxidation, ubiquitination, acetylation, and methylation. Molecular dynamics simulations indicated oxidation-induced rigidity of the myosin head, predicted to compromise the flexibility of the actin-binding and converter domains. Non-force-generating fibers exhibited a unique proteomic signature predicted to enhance myosin motor domain exposure and rigidity.
CONCLUSION: In addition to muscle wasting and myosin loss, abnormal myosin post-translational modifications contribute to muscle weakness in ICU patients with CIM, including the development of muscle fibers incapable of generating contractile force.

Keywords:  critical care; liquid chromatography–tandem mass spectrometry; mechanical ventilation; muscle contraction; skeletal muscle

DOI:  https://doi.org/10.1111/apha.70240
Physiol Rep. 2026 Jun;14(12): e70904

Short-term high-fat feeding induces muscle-type-specific signaling adaptations in skeletal muscle of male rats.

Arata Tsutaki, Hidetaka Imagita, Asumi Yoshida.

  Short-term high-fat diet (HFD) feeding is used to study metabolic dysregulation, yet many rodent models use extreme fat contents that may not reflect physiological conditions. Skeletal muscle responses to short-term HFD also vary by muscle type. We tested whether a physiologically relevant HFD induces muscle-type-specific changes in skeletal muscle signaling and mitochondrial-related proteins. Male Wistar rats were fed a low-fat diet (LFD; 10% energy from fat) or HFD (40% energy from fat) for 4 weeks (n = 5/group). Soleus and extensor digitorum longus (EDL) muscles were analyzed for OXPHOS complexes, mitochondrial dynamics proteins, and ERK1/2 signaling. HFD increased energy intake and visceral adiposity without changing body weight or muscle mass. In soleus, OXPHOS complex II was reduced, whereas other complexes were preserved. In EDL, phosphorylation of ERK1/2 (Thr202/Tyr204) and Drp1 (Ser616) was reduced without changes in total protein abundance. Thus, short-term, physiologically relevant HFD feeding induces muscle-type-specific molecular and signaling adaptations before overt changes in body weight or muscle mass.

Keywords:  ERK signaling; high‐fat diet; mitochondrial dynamics; muscle‐type specificity; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70904
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70322

Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle.

Muhammad Bilal, Le Duc Anh, Nguyen Quynh Phuong, Sana Khalid, Allah Nawaz, Memoona, Muhammad Rahil Aslam, Tomonobu Kado, Yoshiyuki Watanabe, Ayumi Nishimura, Yoshiko Igarashi, Aamir Sharif, Yasuhiro Onogi, Tsutomu Wada, Ryuji Hayashi, Kenichi Hirabayashi, Seiji Yamamoto, Takashi Nakagawa, Hisashi Mori, Isao Usui, Masaru Kato, Shiho Fujisaka, Kazuyuki Tobe.

   BACKGROUNDS: Obesity and diabetes impair the ability of the muscle to regenerate, repair and remodel, resulting in a gradual decrease in muscle mass and function. However, the underlying mechanisms and effective therapeutic strategies remain poorly understood. M2 macrophages within skeletal muscle play an important role in tissue recovery following injury. This study aims to investigate the role of M2 macrophages derived transforming growth factor-beta 1 (Tgf-β1) in regulation of skeletal muscle function under diet-induced obese conditions.
METHODS: An CD206+ M2 macrophage-specific Tgf-β1 gene knockout (Tgf-β1 KO) mouse model was generated by crossing CD206-CreERT2 mice with Tgf-β1f/f mice, followed by tamoxifen administration to induce Tgf-β1 gene deletion. Mice were then placed on a high-fat diet (HFD) for 12 weeks to develop obesity-induced skeletal muscle dysfunction. The study used multiple physiological and molecular analyses, including exercise tolerance, hanging time, grip strength, glucose and insulin tolerance tests, western blotting, RT-qPCR and others.
RESULTS: The present findings demonstrated improved exercise performance, as evidenced by increased running distance twice (p = 0.0008) in Tgf-β1 KO mice. Deletion of CD206+ M2 macrophage-specific Tgf-β1 stimulates fibro-adipogenic progenitors (FAPs), inducing Follistatin (Fst) expression by 1.70-fold (p = 0.04) and follistatin-like protein 1 (Fstl1) by 2.60-fold (p = 0.01) in tibialis anterior (TA), thus enhancing myogenesis. The Tgf-β1 KO mice showed increased muscle fibre type I (Myh7 by 2.40-fold, p = 0.005), muscle fibre type IIa (Myh2 by 1.50-fold, p = 0.003), type IIx (Myh1 by 2.35-fold, p = 0.002) in soleus and type II (Myh4 by 1.76-fold, p = 0.02) in TA. In Tgf-β1 KO mice, insulin-stimulated Akt phosphorylation was significantly increased in adipose tissue by 2.14-fold (p = 0.0003) and in the liver by 1.62-fold (p = 0.01). Besides, the Tgf-β1 KO mice showed increased circulating adiponectin by 1.23 fold (p = 0.003), thereby activating the AMPK/SIRT1/PGC-1α pathway with the phosphorylation level of AMPKα increased by 1.5-fold (p = 0.02), and PGC1α protein level increased by 2.2-fold (p = 0.02) via increased AdipoR1 mRNA expression by 1.8-fold in TA, p = 0.0001 and by 1.8-fold in soleus, p = 0.01 in skeletal muscle, leading to improved mitochondrial function in skeletal muscle.
CONCLUSIONS: The CD206+ M2 macrophage-specific Tgf-β1 deletion ameliorates obesity-induced muscle dysfunction, potentially via two distinct mechanisms. Firstly, it enhances myogenesis by promoting FAP-mediated expression of Fst and Fstl1, thereby augmenting myogenesis-related gene expression in skeletal muscle. Secondly, it also induces adipocytes to produce and secrete adiponectin into the bloodstream, thereby enhancing mitochondrial function via the AMPK/SIRT1/PGC-1α pathway.

Keywords:  M2 macrophage‐derived Tgf‐β1; mitochondrial function; muscle dysfunction; sarcopenic obesity

DOI:  https://doi.org/10.1002/jcsm.70322
Crit Care. 2026 Jun 16.

Critical illness impairs coordinated myogenesis: a prospective longitudinal study of skeletal muscle progenitor cell biology using serial muscle biopsies (SATELLITE study).

Adéla Krajčová, Vlasta Němcová, Pavel Škrha, Lucie Genserová, Andrea Musilová, Michal Fric, Petr Waldauf, František Duška.

   BACKGROUND: Critical illness often causes prolonged weakness, possibly due to impaired skeletal muscle regeneration, but the timing and nature of satellite cell (SC) dysfunction remain unclear. We aimed to determine whether SC depletion and dysfunction are detectable early after intensive care unit admission and describe their pathophysiological nature.
METHODS: In this prospective single-centre observational cohort study, mechanically ventilated adults underwent paired vastus lateralis biopsies within 72 h of ICU admission and again after 7 and 180 days. Isolated satellite cells were studied for proliferation, differentiation and fusion, mitochondrial morphology, respiratory function, substrate oxidation, and selected signalling proteins.
RESULTS: We enrolled 20 healthy control subjects and 33 ICU patients. Twenty three ICU patients survived to day 7 with a repeat biopsy. During 7 days in ICU, the patient developed profound weakness (MRC score 16 [0-32]) and insulin resistance (whole body glucose disposal 4.0 [3.5-5.1] versus 13.8 [8.8-16.1] mg/kg/min in controls). Satellite cell number per fibre was similar in controls and patients at admission (0.106 [0.085-0.129] vs. 0.098 [0.056-0.125]) and after 7 days (0.084 [0.066-0.117]; paired p = 0.784). SC proliferation was lower in older patients (ρ=-0.68 and - 0.49) and associated with lower muscle strength (ρ = 0.55 and 0.62). Myogenic differentiation was transiently impaired at day 0 (fusion index 68.9% [66.3-71.7] vs. 74.0% [70.3-77.1] in controls; p = 0.029). Satellite cell bioenergetics and substrate preferences were broadly preserved. In contrast, a more fragmented mitochondrial phenotype was associated with lower proliferation, lower respiratory performance, and worse muscle strength (ρ≈-0.6 to -0.8), whereas more interconnected morphology was associated with better function (ρ ≈ 0.6-0.7). Out of 10 ICU survivors at day 180, only 7 attended follow up. In those, impaired SF-36 physical score (62.5 [55.0 to 75.0]) and SC proliferation capacity (~50 %), contrasted with improved insulin sensitivity and SC number per fiber (~71 % and ~95% of control values, respectively).
CONCLUSIONS: Critical illness was associated with disturbed satellite cell regenerative programming and altered mitochondrial remodelling rather than early depletion of the satellite cell pool or overt bioenergetic failure. Age was a stronger predictor of early satellite cell dysfunction than disease severity.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT05671614. Registered 4 January 2023.

Keywords:  Critical illness; Muscle stem cells; Myogenesis; Satellite cells; Skeletal muscle regeneration

DOI:  https://doi.org/10.1186/s13054-026-06131-5
Biomed Pharmacother. 2026 Jun 19. pii: S0753-3322(26)00710-9. [Epub ahead of print]201 119674

Administration of Pgk1 missense mutation leads to more effective mitigation of neurodegenerative effects observed in ALS mice and transgenic zebrafish.

Bing-Chang Lee, Jui-Che Tsai, Wei-Zen Chang, Chun-Cheng Wang, Ai-Ling Hour, Chia-Chuan Wang, Huai-Jen Tsai.

  Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons (MNs) with few available therapeutic options. Previous ALS studies demonstrated a decrease in phosphoglycerate kinase 1 (Pgk1) secreted from NogoA-overexpressing muscle cells, thus reducing interaction between extracellular Pgk1 (ePgk1) and neural membranous Enolase 2 (Eno2) with consequent inhibition of neurite outgrowth of MNs (NOMN). The negatively charged 419th aspartic acid of receptor Eno2 (Eno2-D419) is a critical residue interacting with the positively charged 353rd lysine of ligand ePgk1-K353. To strengthen the charge attraction, we mutated ePgk1-K353 to arginine (ePgk1-K353R). Compared to wild-type Pgk1, supplementary mutant Pgk1-K353R proved more effective in increasing NOMN derived from NSC34 neural cells cultured in Sol8-vector condition medium. In vivo, Pgk1-K353R-immersed zebrafish embryos exhibited increased caudal primary MNs branching. Intravenous injection of Pgk1-K353R into ALS-mice exhibited more preservative in innervated neuromuscular junctions in gastrocnemius muscle and diaphragm, increased grip strength, higher rearing frequency, 1.6-fold greater locomotive distance and longer survival. For example, median survival days for the control, Pgk1 and Pgk1-K353R groups were 131, 137.5 and 148, respectively. Collectively, we found a single-amino-acid mutant Pgk1-K353R that exhibits higher efficacy to ameliorate neurodegeneration in ALS-mice by delaying disease progression compared to that driven by wild-type Pgk1. We suggest this outcome might be due to more electrostatic attraction between ePgk1-K353R and Eno2-D419 region predicted by in silico analysis. Therefore, mutant Pgk1-K353R protein should be considered a promising neuroprotective drug for ALS treatment.

Keywords:  ALS disease; Amino acid charge; Motor neurons; Neurodegeneration; Pgk1; Point mutation

DOI:  https://doi.org/10.1016/j.biopha.2026.119674
Nucleus. 2026 Dec;17(1): 2688584

The nucleus as a mechanobiological hub in muscle aging.

Osman Esen, Edmund Battey, Matthew J Stroud, Tyler J Kirby.

  Aging leads to a progressive loss of muscle mass and strength, termed sarcopenia, which is accelerated by inactivity and exacerbated by intrinsic cellular and molecular dysfunctions within the muscle fiber. Central to these changes is mechanotransduction, the process by which mechanical stimuli are converted into biochemical cues critical for protein synthesis, cytoskeletal remodeling, calcium signaling, and metabolism. Recent evidence highlights the nucleus as a key mechanosensory organelle in skeletal muscle. Forces transmitted from the extracellular matrix (ECM) through the cytoskeleton reach the nuclear envelope, where the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and nuclear lamina convert physical stress into gene-regulatory events. Aging may alter these structures, producing changes in nuclear morphology, decreased stiffness, envelope fragility, and compromised transcriptional control. This review examines how the ECM, cytoskeleton, LINC complex, and nuclear lamina change in aged skeletal muscle, proposing that impaired nuclear mechanosignaling contributes to muscle fiber dysfunction during physiological aging.

Keywords:  LINC complex; Skeletal muscle; aging; cytoskeleton; extracellular matrix; mechanotransduction; nuclear lamina; nucleus

DOI:  https://doi.org/10.1080/19491034.2026.2688584
Sci Adv. 2026 Jun 19. 12(25): eaec3505

NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.

Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J McKenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas.

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle-stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated with reduced levels of the mitochondrial RNA polymerase, POLRMT [polymerase (RNA) mitochondrial DNA directed]. We further show that POLRMT is directly modified by NEDDylation, which alters its stability by antagonizing ubiquitylation and degradation. Notably, NEDD8 levels decline with age in both mouse and human oocytes. Together, these findings identify NEDDylation as a regulator of oocyte quality and connect this pathway to mitochondrial transcription in oocytes.

DOI: https://doi.org/10.1126/sciadv.aec3505
Front Cell Infect Microbiol. 2026 ;16 1857062

SARS-CoV-2-induced dysregulation in ADAR editing patterns persists post viral clearance in individuals with mild COVID-19.

Aiswarya Mukundan Nair, Helen Piontkivska.

   Introduction: Innate immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection activates multiple interferon stimulated genes (ISGs), including ADAR1 p150 isoform, which edits adenosine (A) residues within double stranded RNAs in both the virus and the host. In addition to its immune role, ADAR editing also serves as a mechanism of dynamic regulation of transcriptome and proteome diversity. While evidence points to changes in ADAR editing during infection, we do not know whether editing targets change over the course of the infection.
Methods: Here, we explored temporal changes in ADAR expression and editing patterns, across three distinct stages of SARS-CoV-2 infection. Furthermore, we examined whether infection-triggered dysregulation in ADAR editing persists or returns to pre-infection states post-viral clearance using publicly available whole blood RNA sequencing samples from forty-five, age-matched individuals. The individuals selected had no documented comorbidities, developed mild COVID-19, and were sampled across three distinct stages of SARS-CoV-2 infection: pre-, mid-, and post-infection.
Results and discussion: Our results demonstrate dynamic changes in ADAR expression and editing across the three stages. We further identified editing sites that were edited only in one of the three stages of infection within genes involved in immune response pathways, specifically, within neutrophil degranulation pathway genes. Our results demonstrate a consistent trend of elevated ADAR expression and reduced overall ADAR editing within each individual mid-infection. Subsequently, post-infection, though ADAR expression returns to pre-infection levels, ADAR editing remains dysregulated in some individuals. Given that dysregulated ADAR editing could be a mechanistic link between viral infections and sequalae, it is possible that persistent dysregulation of ADAR editing in a subset of recovered individuals contributes to the heterogeneity in disease outcomes seen in individuals post-SARS-CoV-2 infection.

Keywords:  ADAR editing; CHARM trial; RNA editing; SARS-CoV-2; severe acute respiratory syndrome coronavirus 2; transcriptome

DOI:  https://doi.org/10.3389/fcimb.2026.1857062
Sci Adv. 2026 Jun 19. 12(25): eadz3612

Statins promote muscle metabolic danger and NLRP3-mediated myopathy via lower protein-prenylation and YAP.

Nazli Robin, Nicole G Barra, Kevin P Foley, Yujin E Li, Akhilesh K Tamrakar, Danish Patoli, Irena A Rebalka, Tabitha Cree, Kaitlyn Bibby, Khang Nguyen, Rhianna Davis, Darryl Y Chan, Brittany M Duggan, Brandyn D Henriksbo, Megan E Borges, Dana Kukje Zada, Han Fang, Daniel M Marko, Paul Gregorevic, Kevin I Watt, Richard J Mills, Gary Sweeney, Thomas J Hawke, Bénédicte F Py, Jonathan D Schertzer.

Statin intolerance and side effects such as low-level myopathy limit statin use and the dose for optimal cholesterol lowering. We found that priming the NLRP3 inflammasome with bacterial components like lipopolysaccharide lowered the dose of statins that caused side effects in muscle cells. We then built models of low-level statin myopathy and found that muscle cell-autonomous statin-induced myopathy occurs through the NLRP3 inflammasome in vitro and in mice. Statin-induced muscle cell death and higher Atrogin-1 were prevented by blocking NLRP3 or restoring isoprenoids but not cholesterol. Statins reduced glycolysis in muscle cells, which required lower protein prenylation. Statins lowered YAP effector genes and promoted nuclear accumulation of FOXO. Activating YAP, restoring isoprenoids, or blocking NLRP3 mitigated nuclear FOXO accumulation, statin-induced muscle atrophy, and statin-mediated lowering of protein synthesis. These results define a statin-induced myopathy pathway where metabolic danger engages the NLRP3 inflammasome and YAP via lower prenylation independent of cholesterol.

DOI: https://doi.org/10.1126/sciadv.adz3612
Cell Death Dis. 2026 Jun 18.

Sex-linked helicases DDX3X and DDX3Y regulate G-quadruplex-associated stress in neurons.

Rocio Diaz Escarcega, Vijay Kumar M J, Ashlee Arizmendez, Chunfeng Tan, Akihiko Urayama, Sean P Marrelli, Rodrigo Morales, Jeffrey S Wefel, Chunchao Zhang, Louise D McCullough, Nayun Kim, David Monchaud, Sung Yun Jung, Andrey S Tsvetkov.

G-quadruplexes (G4s) are four-stranded nucleic acid structures that regulate virtually all nucleic acid-dependent cellular processes. At present, most functional studies involving G4s have focused on cancer cells. This study investigated how neurons respond to genotoxic stress induced by quarfloxin (CX-3543), a small molecule that stabilizes G4s. We found that quarfloxin treatment induced DNA damage in neurons, with double-strand breaks enriched in the nucleolus. Proteomic analysis revealed that quarfloxin promoted substantial protein changes, affecting networks associated with Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Among the affected proteins, the G4 helicase DDX3X, encoded on the X chromosome, was upregulated, prompting further investigation of DDX3X and its Y-linked homolog DDX3Y in male and female neurons, respectively. RNA sequencing identified DDX3X- and DDX3Y-regulated gene networks involved in DNA damage responses, inflammation, cell cycle regulation, and stress-associated pathways, with notable sex-dependent differences. In human brain tissue, DDX3X expression and nuclear enrichment were increased in neurons from older females compared to younger individuals, with further elevation observed in Alzheimer's disease. Taken together, these findings identify DDX3X and DDX3Y as modulators of neuronal stress responses downstream of G4 stabilization and indicate that their induction is accompanied by activation of DNA damage response genes, as well as cell cycle- and inflammation-associated pathways, suggesting that sustained activation of these pathways may disrupt neuronal homeostasis. Our study provides insight into G4-dependent stress mechanisms in neurons and highlights sex-linked pathways that may contribute to brain aging and neurodegenerative disease vulnerability.

DOI: https://doi.org/10.1038/s41419-026-08971-z
Acta Neuropathol Commun. 2026 Jun 18.

Intrathecal (G4C2)149 delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.

Katelyn A Russell, Amelia A Shahrabi, Suleyman C Akerman, Matthew D Byrne, Jeffrey D Rothstein, Davide Trotti, Brigid K Jensen, Aaron R Haeusler.

  A repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G4C2)149 repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, fewer motor neurons, glial activation, sparse phosphorylated TDP-43 pathology, and increased cryptic TDP-43 splicing. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.

Keywords:  ALS; ALS/FTD; C9orf72; C9orf72 repeat expansions; FTD; Motor neuron disease; Mouse models; Neurodegenerative disease

DOI:  https://doi.org/10.1186/s40478-026-02341-8