bims-musmir 2025-12-07 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–12–07
thirteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.
Non-muscle myosin IIC predominantly expressed in the slow-twitch skeletal muscles impedes age-related muscle weakness.
Critical role of mitochondrial aconitase in skeletal muscle maturation.
Myostatin, activin-A and follistatin are produced by the tumor in head and neck cancer and likely contribute to sarcopenia: a case-control, cross-sectional exploratory study.
Postmenopausal sarcopenia and Alzheimer's disease: The interplay of mitochondria, insulin resistance, and myokines.
Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.
C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.
Synaptic Vesicle Exocytosis and Endocytosis in Motor Nerve Endings of Transgenic Mice Modeling Amyotrophic Lateral Sclerosis upon Antioxidant Treatment and Gene-Cell Therapy.
Nimbolide inhibits NLRP3 inflammasome activation via blocking NEK7-NLRP3 interaction and alleviates sepsis-induced lung injury.
Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.
SYNE1 Deficiency Manifesting Primarily With Motor Neuron Disease.

Nat Metab. 2025 Dec 03.

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.

Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A Reisz, Angelo D'Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo.

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.

DOI: https://doi.org/10.1038/s42255-025-01412-9
Skelet Muscle. 2025 Dec 05.

Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.

Nathan Serrano, Pieter Jan Koopmans, Kevin A Murach.

Non-peripheral (displaced) myonuclei are characteristic of skeletal muscle pathology and severe injury but also appear after exercise and with aging. Displaced myonuclei are typically attributed to the activity of muscle stem cells, or satellite cells. We sought to address whether displaced myonuclei in adult skeletal muscle are exclusively from an exogenous source such as satellite cells or can result from resident myonuclear migration. To address this question, we used a murine recombination-independent muscle fibre-specific doxycycline-inducible fluorescent myonuclear labelling approach, EdU stem cell fate tracking, two durations of plantaris muscle mechanical overload (MOV, 3 days and 7 days), and fluorescent histology. Our findings show that: 1) displaced myonuclei emerge early during MOV in adult mice, 2) resident myonuclear movement occurs rapidly during MOV, and 3) the contribution of resident versus exogenous displaced myonuclei depends on the preferential effects of MOV for specific fibre types or fibre sizes with a given MOV duration. These observations provide fundamental insights on myonuclear motility in response to stress in vivo and reframe our understanding of how a recognized feature of mammalian skeletal muscle can emerge in response to stressors such as mechanical loading.

DOI: https://doi.org/10.1186/s13395-025-00407-0
PLoS One. 2025 ;20(12): e0337708

Non-muscle myosin IIC predominantly expressed in the slow-twitch skeletal muscles impedes age-related muscle weakness.

Hiroki Hamaguchi, Shino Hiraoka, Kun Tang, Haonan Zhu, Yoshitaka Mita, Yasuro Furuichi, Nobuharu L Fujii, Yasuko Manabe.

Skeletal muscle expresses three types of non-muscle myosin (NM) II in addition to skeletal type myosin. While immature myoblasts have been reported to express NMIIA and NMIIB, playing roles in cell morphology, the specific localization and function of NMIIC in skeletal muscle cells remain unclear. In this study, we aimed to investigate the expression pattern and the physiological role of NMIIC in skeletal muscle. NMIIC was specifically expressed in the slow-twitch muscles such as soleus, which primarily consists of type I and type IIa fibers, and its expression increased as muscle differentiation progressed. To explore the function of NMIIC in skeletal muscle, we used whole-body NMIIC knockout (KO) mice. Myofiber size was slightly but significantly decreased in the soleus of young (18-20-week-old) NMIIC KO mice. However, contractile force of the isolated soleus muscle in the NMIIC KO mice did not differ from that of wild-type mice, suggesting that the slight reduction in fiber size has limited physiological significance at this age. Interestingly, in 81-week-old NMIIC KO mice, soleus contractile force was significantly reduced despite no difference in fiber size between aged wild-type and NMIIC KO mice. Notably, NMIIC expression levels were higher in aged than young mice. These findings suggest that while NMIIC has minimal impact on skeletal muscle function under young and healthy conditions, it may play a crucial role in maintaining muscle function when muscle is compromised at age.

DOI: https://doi.org/10.1371/journal.pone.0337708
Sci Rep. 2025 Dec 02. 15(1): 42957

Critical role of mitochondrial aconitase in skeletal muscle maturation.

Tomoya Fukawa, Miho Takata, Kota Kishida, Kosuke Sugiura, Minori Suzuki, Haruka Tsuda, Iori Sakakibara, Takayuki Uchida, Md Mizanur Rahman, Anayt Ulla, Koichi Sairyo, Takahiko Sato, Madoka Ikemoto-Uezumi, Akiyoshi Uezumi, Takeshi Nikawa.

  Skeletal muscle dynamically regulates protein synthesis and degradation through metabolic responses to external stimuli. In the absence of mechanical load, this normal metabolic response is impaired, leading to muscle atrophy. Previous studies have suggested that mitochondrial dysfunction occurs under unloaded conditions. In this study, we focused on aconitase 2 (Aco2), a mitochondrial protein known to contain an iron-sulfur cluster and function as a metabolic sensor. We generated skeletal muscle-specific Aco2 knockout (cKO) mice to investigate its role in muscle function. Although these mice appeared grossly normal, they died shortly after birth. Analysis of the diaphragm muscle revealed signs of muscle fiber atrophy and impaired muscle maturation. Besides these signs of immaturity, abnormal muscle cells exhibiting disrupted sarcomere structures were frequently observed. Furthermore, these cells showed a marked increase in the apoptotic marker Active Caspase-3, indicating that Aco2 deficiency induces muscle cell death. These findings suggest that Aco2 plays a critical role in skeletal muscle maturation and maintenance of muscle homeostasis. Moreover, these findings highlighted the potential involvement of Aco2 in disuse muscle atrophy and its utility as a therapeutic target.

Keywords:  Aconitase 2-knockout mice; Apoptosis; Mitochondrial dysfunction; Sarcomere disruption; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-025-25560-w
Clin Nutr ESPEN. 2025 Dec 01. pii: S2405-4577(25)03153-5. [Epub ahead of print]

Myostatin, activin-A and follistatin are produced by the tumor in head and neck cancer and likely contribute to sarcopenia: a case-control, cross-sectional exploratory study.

Nicolas Saroul, Alexis Dissard, Bruno Pereira, Thierry Mom, Yves Boirie, Laurent Gilain, Mathilde Puechmaille, Veronique Patrac, Jérôme Salles, Stéphane Walrand.

   BACKGROUND AND AIMS: Myostatin (M), activin-A (A) and follistatin (F), three TGF-β superfamily members, play a role in cancer sarcopenia. The aim of our study was to assess the association of MAF in head and neck cancer (HNC) skeletal muscle loss.
MATERIALS AND METHODS: This prospective study involved 55 patients, 32 with HNC and 23 controls. The patients underwent a full nutritional assessment just before surgery. Tumor, muscle and plasma were harvested at the time of surgery. Plasma was harvested a second time 7 days after the procedure. Tumor explants were cultured and MAF were measured in the incubation medium.
RESULTS: A and F plasma levels were higher in cancer patients compared to control (320 vs. 203 pg/ml, p <0.001, ES= 0.96 95% CI [0.40; 1.52] and 3593 vs 2148 pg/ml, p <0.001, ES = 1.10 95%CI [0.53; 1.66], respectively) and M plasma level lower (1542 vs. 2100 pg/ml, p = 0.01, ES = -0.70 95%CI [-1.24; -0.15]). M plasma level was correlated with the skeletal muscle index at the third lumbar vertebra (r=0.44; p<0.05) and negatively correlated with weight loss (r=-0.65; p<0.05) and the C Reactive protein level (-0.44; p=0.02). At the seventh postoperative day (D), A was increased (D7 vs D0) in the cancer group (379 vs 320 pg /ml; p <0.001) while the concentrations of M and F were unchanged from the presurgical level. There was no difference between groups in the transcript levels of M and A in skeletal muscles. MAF were systematically detected in the tumor incubation medium with no correlation between tumor incubation medium level and plasma level at D0.
CONCLUSION: The MAF secretory profile is modified in HNC. In particular, A seems to play a role in muscle loss while F protects against skeletal muscle mass loss.

Keywords:  CT scan; activin A; bioelectrical impedance analysis (BIA); cachexia; cancer; follistatin; head and neck cancer; myostatin; sarcopenia; skeletal muscle; skeletal muscle index

DOI:  https://doi.org/10.1016/j.clnesp.2025.11.159
Neurosci Biobehav Rev. 2025 Nov 29. pii: S0149-7634(25)00502-0. [Epub ahead of print]180 106501

Postmenopausal sarcopenia and Alzheimer's disease: The interplay of mitochondria, insulin resistance, and myokines.

Fardous Farhana, Most Arifa Sultana, Raksa Andalib Hia, Vijay Hegde.

  As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60 % of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.

Keywords:  Alzheimer’s disease; Insulin resistance; Menopause; Mitochondrial dysfunction; Myokines; Oxidative stress; Sarcopenia

DOI:  https://doi.org/10.1016/j.neubiorev.2025.106501
bioRxiv. 2025 Nov 19. pii: 2025.11.19.688750. [Epub ahead of print]

Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.

Young-Seung Lee, Hee Soo Kim, Phuc L Nguyen, Junhyeong Lee, Dong-Il Kim, Jeongmin Lee, Changjong Moon, Kyoung-Oh Cho, Byung-Eun Kim, Jiyun Ahn, Timothy F Osborne, Taner Duysak, Jeong-Sun Kim, Chang Hwa Jung, Tae-Il Jeon.

Copper is an essential trace element required for mitochondrial respiration and cellular metabolism, yet its role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice leads to copper deficiency, resulting in exercise intolerance, metabolic dysfunction, and hallmarks of mitochondrial myopathy, including ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Copper deficiency disrupted electron transport chain proteome and induced mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator of mitochondrial copper distribution and morphology. Restoring copper levels via the copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings highlight MTCH2 as a key mediator of a critical link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.

DOI: https://doi.org/10.1101/2025.11.19.688750
Mol Metab. 2025 Nov 29. pii: S2212-8778(25)00201-7. [Epub ahead of print] 102294

Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle.

Dipsikha Biswas, Ever Espino-Gonzalez, Danial Ahwazi, Jordana B Freemantle, Amy M Ehrlich, Charline Jomard, Jonas Brorson, Agnete N Schou, Jean Farup, Julien Gondin, Jesper Just, Marc Foretz, Jonas T Treebak, Marianne Agerholm, Kei Sakamoto.

   OBJECTIVE: Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.
METHODS: Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1-/-/γ3-/-) and single knockout (imγ1-/- and imγ3-/-) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.
RESULTS: snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1-/-/γ3-/- muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3-/-, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1-/- mice.
CONCLUSIONS: While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.

Keywords:  AICAR; AMP-activated protein kinase; MK-8722; Single nucleus RNA sequencing; glucose uptake

DOI:  https://doi.org/10.1016/j.molmet.2025.102294
Front Mol Neurosci. 2025 ;18 1671906

C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.

Seham Almalki, Mohamed Salama, Matthew J Taylor, Zubair Ahmed, Richard I Tuxworth.

  The G4C2 repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While healthy individuals have fewer than 30 repeats, affected patients may carry hundreds to thousands. This expansion accounts for approximately 40% of familial ALS and 25% of familial FTD cases, and between 5 and 10% cases of sporadic ALS and FTD. Three overlapping pathological mechanisms have been proposed for the C9orf72 expansion: loss of function due to protein deficiency, gain of function through RNA foci, and the production of toxic dipeptide repeat proteins (DPRs) via repeat-associated non-ATG (RAN) translation. This systematic review investigates the role of DNA damage in C9orf72-related ALS-FTD. Analysis of twelve peer-reviewed studies showed that C9orf72 repeat expansions and DPRs compromise genome stability across four experimental models: human cell lines, induced pluripotent stem cell-derived neurons, rodent neurons, and postmortem tissue. We identified four mechanisms underlying DNA damage accumulation: disruption of the ATM pathway, impairment of DNA repair efficiency, formation of R-loops, and mitochondrial dysfunction with oxidative stress. In addition, several consequences of DNA damage were identified, including misrepair-mediated repeat expansion and activation of STING pathway. These findings highlight the key role of DNA damage in C9orf72-related pathology. Consistent with this, targeting DNA damage response factors extended lifespan and improved motor function in mouse models. This review highlights the contribution of DNA damage to C9orf72 pathology and suggest new therapeutic avenues, including personalized approaches based on genetic background.

Keywords:  ALS; ALS-FTD; C9orf72; DDR; DNA damage; DNA repair; FTD

DOI:  https://doi.org/10.3389/fnmol.2025.1671906
Dokl Biol Sci. 2025 Dec 02.

Synaptic Vesicle Exocytosis and Endocytosis in Motor Nerve Endings of Transgenic Mice Modeling Amyotrophic Lateral Sclerosis upon Antioxidant Treatment and Gene-Cell Therapy.

P N Grigoryev, A L Zefirov, R D Mukhamedzyanov, I I Salafutdinov, R R Islamov, M A Mukhamedyarov.

  Exocytosis and endocytosis of synaptic vesicles were studied in experiments with motor nerve endings of diaphragm neuromuscular preparations isolated from transgenic mice with a model of amyotrophic lateral sclerosis (ALS); treatment simulated antioxidant (edaravone) and gene-cell (umbilical cord blood mononuclear cells (UCB-MNCs) producing VEGF, GDNF, and NCAM) therapies. None of the treatments was found to significantly change the FM 1-43 fluorescent dye loading due to synaptic vesicle endocytosis. Gene-cell therapy increased the rate of dye unloading due to synaptic vesicle exocytosis, while antioxidant therapy did not change the FM 1-43 unloading rate. Based on the findings, gene-cell therapy was assumed to facilitate synaptic vesicle transport to release sites upon high-frequency stimulation in motor nerve endings of transgenic mice.

Keywords:  amyotrophic lateral sclerosis; antioxidant therapy; exocytosis and endocytosis of synaptic vesicles; gene-cell therapy; neuromuscular junction; transgenic mice

DOI:  https://doi.org/10.1134/S0012496625600356
Int Immunopharmacol. 2025 Nov 29. pii: S1567-5769(25)01942-3. [Epub ahead of print]168(Pt 2): 115954

Nimbolide inhibits NLRP3 inflammasome activation via blocking NEK7-NLRP3 interaction and alleviates sepsis-induced lung injury.

XueYi Wang, JunMei Li, BoWen Yu, HuanHuan Gong, ZhanChuan Li, Yang Bai.

   BACKGROUND: Sepsis-associated acute lung injury (ALI) remains a critical clinical challenge with limited therapeutic options. The NLRP3 inflammasome drives pathological inflammation in ALI, yet clinical translation of existing inhibitors is hindered by toxicity. Natural products offer safer alternatives, but their mechanisms in targeting NLRP3 assembly are poorly defined.
METHODS: We screened a natural compound library for NLRP3 inhibitors using LPS/nigericin-stimulated murine peritoneal macrophages, measuring IL-1β release by ELISA. Mechanistic studies included immunoprecipitation (NEK7-NLRP3/ASC-NLRP3 interactions), ASC oligomerization/speck formation assays, DARTS, CETSA, and molecular docking. In vivo efficacy was evaluated in LPS-induced ALI and endotoxemia mouse models (histopathology, cytokine analysis, immunoblotting).
RESULTS: Nimbolide was identified as a potent NLRP3 inhibitor. It dose-dependently suppressed IL-1β secretion and caspase-1/GSDMD cleavage in murine/human (THP-1) macrophages, without affecting AIM2/NLRC4 inflammasomes or TNF-α production. Mechanistically, Nimbolide disrupted NEK7-NLRP3 binding and ASC oligomerization, thereby blocking NLRP3 inflammasome assembly. Further investigations revealed that Nimbolide enhanced the thermal stability of NLRP3 as demonstrated by the cell thermal shift assay (CETSA), conferred protease resistance as evidenced by the drug affinity responsive target stability (DARTS) assay, and exhibited high-affinity binding to NLRP3 with a binding energy of -7.62 kcal/mol through molecular docking studies. These results collectively suggest that Nimbolide can directly bind to NLRP3. In vivo, Nimbolide reduced pulmonary IL-1β levels, suppressed GSDMD cleavage, and attenuated lung injury pathology.
CONCLUSION: Nimbolide is a new natural inhibitor that selectively targets the NLRP3 interface and block NLRP3 inflammasome activation, offering a promising therapeutic strategy for NLRP3-driven inflammatory disorders like sepsis-associated ALI.

Keywords:  Acute lung injury; NLRP3 inflammasome; Nimbolide; Sepsis

DOI:  https://doi.org/10.1016/j.intimp.2025.115954
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2508707122

Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle-tumor metabolic competition.

Brooks P Leitner, Andin E Fosam, Won D Lee, Kaylee Zilinger, Susana C B R Nakandakari, Xinyi Zhang, Rafael C Gaspar, Wanling Zhu, Curtis J Perry, Joshua D Rabinowitz, Rachel J Perry.

  Higher exercise capacity and regular exercise training improve cancer prognosis at all stages of disease. However, the metabolic adaptations to aerobic exercise training that mediate tumor-host interactions are poorly understood. Here, we demonstrate that voluntary wheel running slows tumor growth and repartitions glucose uptake and oxidation to skeletal and cardiac muscle and away from breast and melanoma tumors in mice. Further, prehabilitation induces repartitioning of glucose metabolism in obese mice: Uptake and oxidation of glucose are enhanced in skeletal and cardiac muscle, and reduced in tumors. These increases in muscle glucose metabolism and reductions in tumor glucose metabolism, correlated with slower tumor progression. Using [U-13C6] glucose infusion, we show that exercise increases the fractional contribution of glucose to oxidative metabolism in muscle while reducing it in tumors, suggesting that aerobic exercise shifts systemic glucose metabolism away from the tumor microenvironment and toward metabolically active tissues. Transcriptional analysis revealed downregulation of mTOR signaling in tumors from exercised mice. Collectively, our findings suggest that voluntary exercise may suppress tumor progression by enhancing host tissue glucose oxidation and limiting tumor glucose availability, supporting a model in which exercise-induced metabolic competition constrains tumor energetics.

Keywords:  breast cancer; exercise; melanoma; tumor metabolism

DOI:  https://doi.org/10.1073/pnas.2508707122
Neurol Genet. 2025 Dec;11(6): e200306

SYNE1 Deficiency Manifesting Primarily With Motor Neuron Disease.

Henriette V F Senghor, Raúl Domínguez Rubio, Carla Marco, Ainara Salazar-Villacorta, Ariadna Padró-Miquel, Sergi Beltran, Leslie Matalonga, Fabián Márquez, Hamath Abdoul Sy, Mamadou Sy, Monica Povedano, Amadou Gallo Diop, Moustapha Ndiaye, Pedro M Rodríguez Cruz.

Background and Objectives: SYNE1 deficiency is an autosomal recessive disorder with a broad phenotypic spectrum, most commonly presenting as adult-onset cerebellar ataxia with or without motor neuron dysfunction. We aimed to expand this spectrum by describing the clinical and genetic findings in 2 unrelated families with early-onset motor neuron disease and virtually no cerebellar signs over time.
Methods: We performed detailed clinical, neurophysiologic, and genetic studies of 2 unrelated families with juvenile amyotrophic lateral sclerosis (ALS) and biallelic variants in SYNE1.
Results: The phenotypes of both families showed onset of symptoms in childhood or adolescence, with signs of upper and lower motor neuron dysfunction in multiple territories suggestive of juvenile ALS. Patients developed progressive muscle weakness, eventually leading to respiratory distress and bulbar signs. Whole-exome sequencing identified SYNE1 biallelic truncating variants in both families: a homozygous nonsense variant, c.23131C>T (p.Gln7711*), in Family 1, and a novel homozygous splice-site variant, c.17851-1G>A, in Family 2. Notably, mild or no cerebellar manifestations were observed during the follow-up.
Discussion: This report highlights a novel phenotype of SYNE1 deficiency characterized by early-onset motor neuron disease and virtually no cerebellar manifestations, broadening the phenotypic spectrum of this complex neurodegenerative disease. These findings support investigating SYNE1 variants in juvenile ALS and including SYNE1 in motor neuron disease gene panels.

DOI: https://doi.org/10.1212/NXG.0000000000200306