bims-musmir 2026-05-31 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–05–31
thirteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Regulatory mechanisms of mitochondrial function by cancer-derived exosomes in cachexia.
Skeletal Muscle miRNA Patterns in High-Altitude Trekkers: Exploratory Identification of Molecular Signatures of Cellular and Endocrine Adaptation.
Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
Skeletal muscle-specific myostatin overexpression promotes muscle oxidative capacity and fatigue resistance in transgenic mice.
Myonuclear Dynamics After Skeletal Muscle Surgical Injury.
Inhibition of TWEAK/Fn14 Ameliorates Sarcopenic Obesity by Restoring Mitochondrial Biogenesis via the AMPK/SIRT1/PGC-1α Axis.
Multicellular senescence impairs skeletal muscle recovery following disuse in aging.
Sepsis Dysregulates Mitochondrial microRNA and Biogenesis in the Diaphragm but Not Limb Muscle.
Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
RYR1+ skeletal muscle-derived extracellular vesicles are exercise responsive and associated with insulin action.
Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.
Single-Cell Proteomics Decodes the Cellular Response to Lysosomal Storage in C. elegans Coelomocytes.
RNA-centric approaches in amyotrophic lateral sclerosis: prospects for future therapeutics.

Front Oncol. 2026 ;16 1715589

Regulatory mechanisms of mitochondrial function by cancer-derived exosomes in cachexia.

Ryotaro Tomida, Keisuke Ozaki, Yukako Tanaka, Rina Komatsu, Syuya Hirata, Takayuki Uchida, Junya Furukawa, Takeshi Nikawa, Tomoya Fukawa.

   Background: Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting and impaired response to conventional nutritional support, affecting up to 80% of advanced cancer patients and contributing to poor prognosis. Excessive fatty acid oxidation and mitochondrial reactive oxygen species (ROS) generation have been implicated in cachexia-associated muscle atrophy, but the underlying mechanisms remain unclear.
Methods and results: We investigated the role of cancer cell-derived exosomes in metabolic alterations of skeletal muscle cells. Exosomes from a pro-cachectic renal carcinoma cell line (RXF393) induced myotube atrophy, enhanced mitochondrial ROS production, impaired mitochondrial respiration, and reduced expression of isocitrate dehydrogenase 2 (IDH2) and respiratory chain complex subunits compared to observations in non-cachectic controls. miRNA profiling identified enrichment of miR-1260b in pro-cachectic exosomes, and transfection with a miR-1260b mimic reproduced these phenotypes, including IDH2 downregulation, impaired antioxidant defense, and mitochondrial dysfunction.
Conclusion: These findings demonstrate that cancer-derived exosomal miR-1260b suppresses IDH2, disrupts mitochondrial redox balance, and promotes muscle wasting. This study reveals a mechanistic link between exosomal miRNAs and mitochondrial dysfunction in cancer cachexia and suggests that maintaining mitochondrial redox homeostasis may represent a novel therapeutic strategy.

Keywords:  cancer cachexia; exosome; isocitrate dehydrogenase 2; miR-1260b; mitochondrial dysfunction; reactive oxygen species; renal cell carcinoma

DOI:  https://doi.org/10.3389/fonc.2026.1715589
Biomolecules. 2026 May 01. pii: 668. [Epub ahead of print]16(5):

Skeletal Muscle miRNA Patterns in High-Altitude Trekkers: Exploratory Identification of Molecular Signatures of Cellular and Endocrine Adaptation.

Tiziana Pietrangelo, Paolo Cocci, Danilo Bondi, Vittore Verratti, Carmen Santangelo, Lorenzo Marramiero, Francesco Alessandro Palermo.

  Exposure to high-altitude hypoxia leads to complex physiological and molecular adaptations, particularly in skeletal muscle. MicroRNAs (miRNAs), including muscle-enriched (myomiRNAs) and hypoxia-responsive (hypoxamiRNAs), play critical roles in regulating these responses. We investigated miRNA expression changes in the skeletal muscle of healthy, non-smoking Italian adults (mean age 36.7 ± 12.4 years) participating in the Himalayan expedition "Lobuche Peak-Pyramid Exploration & Physiology" conducted in the Sagaramāthā (Mount Everest) National Park, Nepal. The peak overnight stay altitude was ≈5000 m at the Pyramid International Laboratory-Observatory. Muscle biopsies were taken before and after the expedition from Vastus lateralis, at one-third of the distance from the upper margin of the rotula to the anterior superior iliac spine. Small RNA sequencing was used to profile differentially expressed miRNAs. Several miRNAs were differentially expressed (exploratory analysis), suggesting potential involvement in hypoxia-related adaptation. These encompass both canonical myomiRNAs (e.g., miR-206, miR-486-5p) and hypoxamiRNAs (e.g., miR-378a-5p, miR-199a-3p, let-7b-5p). In enrichment analysis, we found several connections between miRNAs and pathways that may play a role in physiological regeneration or differentiation in muscle cells. Among functions, focal adhesion (p-value = 0.001), regulation of actin cytoskeleton (p-value = 0.026), Rap-1 (p-value = 0.007), cAMP (p-value = 0.017), MAPK (p-value = 0.019), and Hippo (p-value = <0.001) signaling pathways were predicted to be the most targeted. These findings provide preliminary insights into physiological adaptation, requiring confirmation in larger and controlled cohorts.

Keywords:  biomarkers; extreme environments; high-altitude hypoxia; microRNA (miRNA); skeletal muscle

DOI:  https://doi.org/10.3390/biom16050668
Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):

Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.

Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.

  To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.

Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response

DOI:  https://doi.org/10.3390/muscles5020039
Exp Physiol. 2026 May 28.

Skeletal muscle-specific myostatin overexpression promotes muscle oxidative capacity and fatigue resistance in transgenic mice.

Andy V Khamoui, Andrea Abraham, Janos Porszasz, Istvan Kovanecz, Silvana Constantinescu, Harry B Rossiter, Suzanne Reisz-Porszasz.

  In addition to controlling muscle mass, myostatin may support oxidative metabolism and endurance. Loss of function through gene knockout or post-natal blockade generally lowers muscle oxidative capacity and increases fatigability. These observations imply that myostatin activation could promote a more oxidative and less fatigable muscle phenotype. Gain-of-function approaches that activate myostatin in vivo, however, are largely absent. To test whether myostatin promotes oxidative metabolism in muscle, we constructed transgenic (TG) mice with myostatin (Mstn) gene overexpression restricted to skeletal muscle by inserting an Mstn cDNA construct under the MCK promoter to drive muscle-specific expression of recombinant myostatin protein. On standard diet, TG had greater oxidative fibre expression, greater coupled maximal mitochondrial oxidative phosphorylation (OXPHOS), and increased in situ muscle fatigue resistance. Untargeted metabolomics identified greater stored carbohydrate and glycolytic intermediates in TG muscle, lower lactate/pyruvate and lower AMP that together indicate TG muscle to be energetically primed for carbohydrate-fuelled OXPHOS. Further, TG had enhanced synthesis of spermidine, a polyamine and autophagy inducer implicated in mitochondrial quality control and geroprotection, and large changes in polyunsaturated fatty acid composition with reduced long-chain saturated fat. When challenged by lipid overload, TG displayed some features of intolerance related to glucose clearance and contractility, but also compelling signs of resilience including maintenance of mitochondrial respiratory control and running critical power. Together, these data show that myostatin is not only a regulator of skeletal muscle mass but a central mediator of diverse metabolic pathways that reinforce muscle homeostasis and organismal resilience including carbohydrate metabolism, bioactive lipids, polyamine compounds and mitochondrial respiration.

Keywords:  metabolism; mitochondria; mouse; muscle fatigue; muscle physiology; oxidative phosphorylation

DOI:  https://doi.org/10.1113/EP093775
bioRxiv. 2026 May 13. pii: 2026.05.12.724630. [Epub ahead of print]

Myonuclear Dynamics After Skeletal Muscle Surgical Injury.

Micah Goeke, Nathan Serrano, Pieter Jan Koopmans, Kevin A Murach.

A hallmark of damaged skeletal muscle fibers is displaced myonuclei that are no longer peripherally positioned. Displaced myonuclei are dogmatically thought to be derived exclusively from muscle stem cell (satellite cell) fusion. Using a surgical resection muscle injury model and in vivo recombination-independent resident myonuclear labeling, we detail the prevalence, time course, and origin of displaced myonuclei in response to a non-chemically-mediated muscle trauma. We found that: 1) non-satellite cell-derived (resident) displaced myonuclei emerge seven days after surgical injury in similar proportion to exogenous (satellite cell-derived) displaced myonuclei in intact muscle fibers, with a biased prevalence in myosin heavy chain IIB muscle fibers, 2) muscle fibers with multiple (≥2) displaced resident myonuclei was an unexpected but noteworthy feature of muscle fibers 7 days after injury, 3) embryonic myosin-expressing fibers at seven days post-surgery expectedly contain predominantly satellite-cell derived displaced myonuclei, but a subset have displaced resident myonuclei, and 4) satellite cell numbers in intact muscle do not increase until 7 days post-surgery. These data may help inform whether to target satellite cell-initiated processes, myonuclear-initiated processes, or both to facilitate muscle fiber injury repair. This information could lead to more effective therapeutic strategies for treating muscle trauma.

DOI: https://doi.org/10.64898/2026.05.12.724630
Diabetes Metab Syndr Obes. 2026 ;19 596507

Inhibition of TWEAK/Fn14 Ameliorates Sarcopenic Obesity by Restoring Mitochondrial Biogenesis via the AMPK/SIRT1/PGC-1α Axis.

Saiyare Xuekelati, Zhuoya Maimaitiwusiman, Yanying Guo, Shuke Guo, Qihong Xu, Jiayu Ke, Lei Xu, Yining Yang, Hongmei Wang.

   Purpose: Sarcopenic obesity (SO) represents a critical geriatric syndrome where muscle atrophy and obesity synergistically exacerbate metabolic dysfunction. While the TWEAK/Fn14 pathway is a known regulator of muscle wasting, its specific role and therapeutic potential in the pathogenesis of SO remain unclear.
Methods: To mimic the lipid-rich microenvironment of SO, we utilized a "PrePA-Diff" in vitro model where C2C12 myoblasts were exposed to palmitic acid prior to differentiation. In vivo, SO was established by feeding aged (18-month-old) male C57BL/6 mice a high-fat diet (HFD) for 12 weeks. Subsequently, intramuscular injection of Adeno-associated virus (AAV)-shRNA was employed to specifically inhibit TWEAK expression in skeletal muscle. Mitochondrial function, inflammatory profiles, and signaling pathways were assessed using qPCR, Western blotting, ELISA, and functional assays.
Results: Our results demonstrate that TWEAK inhibition effectively reverses the SO phenotype, characterized by improved grip strength, reduced adiposity, and lowered systemic inflammation and lipid levels. At the cellular level, TWEAK silencing rescued mitochondrial bioenergetics, indicated by enhanced ATP production and suppressed reactive oxygen species (ROS) generation and calcium influx. Molecularly, these protective effects were accompanied by the downregulation of p38 MAPK phosphorylation and the reactivation of the AMPK/SIRT1/PGC-1α signaling axis, a key driver of mitochondrial biogenesis.
Conclusion: Our study identifies the TWEAK/Fn14 axis as a pivotal driver of SO pathology. We conclude that inhibiting TWEAK ameliorates sarcopenic obesity by restoring mitochondrial homeostasis via AMPK/SIRT1/PGC-1α signaling, highlighting TWEAK/Fn14 as a novel therapeutic target for age-related musculoskeletal and metabolic decline.

Keywords:  TWEAK; aging; mitochondrial function; sarcopenic obesity; skeletal muscle

DOI:  https://doi.org/10.2147/DMSO.S596507
Sci Adv. 2026 May 29. 12(22): eaed5255

Multicellular senescence impairs skeletal muscle recovery following disuse in aging.

Paul-Emile Bourrant, Elena M Yee, Zachary J Fennel, Robert J Castro, Chad M Skiles, Jonathan J Petrocelli, Naomi M M P de Hart, Lisa A Lesniewski, Anna E Beaudin, Katsuhiko Funai, Christopher S Fry, Micah J Drummond.

Aged skeletal muscle has a diminished capacity to recover after disuse. Although muscle regrowth requires coordinated interactions between immune and progenitor cells, the mechanisms of impaired remodeling in aged skeletal muscle remain poorly understood yet possibly involve the accumulation of senescent cells. We used a flow cytometry approach coupled with scRNAseq to determine the muscle senescent cell identity and transcriptional landscape during skeletal muscle recovery following disuse atrophy. Young and aged mice underwent 14 days of hindlimb unloading followed by reloading (7 or 14 days). At recovery, old mice showed smaller myofibers and abnormal muscle macrophage dynamics corresponding to greater collagen content. These outcomes coincided with elevated markers of muscle senescence (p21 and γH2AX) and increased SPiDER-β-Gal+ cells, which inversely correlated with muscle mass. Single-cell resolution of SPiDER+ cells unmasked several senescent interstitial muscle vascular and stromal populations. Senescent interstitial cell populations were enriched in aged muscle and displayed a senescence-associated secretory phenotype (SASP) across multiple stromal, vascular, and immune cell types. Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse. These findings identify a multicellular senescence environment within the muscle interstitial niche as a hallmark of impaired muscle recovery following disuse.

DOI: https://doi.org/10.1126/sciadv.aed5255
Int J Mol Sci. 2026 May 09. pii: 4222. [Epub ahead of print]27(10):

Sepsis Dysregulates Mitochondrial microRNA and Biogenesis in the Diaphragm but Not Limb Muscle.

Luther Gill, Patricia Molina, Liz Simon.

  Diaphragm dysfunction that leads to respiratory failure is a significant clinical consequence of sepsis-induced critical illness. Diaphragm muscle weakness contributes to morbidity and mortality in these individuals in part due to impaired mitochondrial function. Restoring normal mitochondrial biogenesis is associated with improved survival and physical function. Therefore, identifying reliable biomarkers of mitochondrial dysfunction in diaphragm muscle will allow for more focused and targeted interventions designed to improve the morbidity of critically ill patients. We used a rodent cecal-ligation and puncture (CLP) model to mimic a moderate grade of sepsis. The diaphragm muscle was harvested from adult mice 48 h following CLP (n = 6) or a sham CLP procedure (n = 6). Our primary finding was that moderate grade CLP increases expression of mitochondria-associated microRNA in the diaphragm. Correspondingly, genes associated with mitochondrial biogenesis decreased. Our study provides evidence for sepsis-mediated dysregulation of mitochondrial homeostasis. This may play a role in diaphragm muscle dysfunction, respiratory failure, and difficult weaning from mechanical ventilation in sepsis-induced critical illness.

Keywords:  diaphragm muscle; microRNA; mitochondrial dysregulation

DOI:  https://doi.org/10.3390/ijms27104222
Commun Biol. 2026 May 27.

Mapping the GDF15 arm of the integrated stress response in human cells and tissues.

Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.

Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.

DOI: https://doi.org/10.1038/s42003-026-10312-x
J Transl Med. 2026 May 26. pii: 707. [Epub ahead of print]24(1):

RYR1+ skeletal muscle-derived extracellular vesicles are exercise responsive and associated with insulin action.

Xin Zhang, Christopher G Vann, David B Bartlett, Alastair Khodabukus, George A Truskey, Nenad Bursac, Joseph A Houmard, Johanna L Johnson, Kim M Huffman, Brian J Andonian, William E Kraus, Virginia Byers Kraus.

   BACKGROUND: Skeletal muscle is a central regulator of insulin sensitivity and glucose homeostasis. The ryanodine receptor 1 (RYR1) is highly expressed in skeletal muscle and plays a key role in myogenic differentiation. We hypothesize that RYR1+ extracellular vesicles (EVs) represent a skeletal muscle-derived EV subpopulation whose abundance and small RNA (smRNA) cargo are associated with aging, insulin action, and exercise responsiveness.
METHODS: We tested this hypothesis through in vitro analyses of smRNAs of skeletal muscle-derived EVs and in vivo evaluation of their exercise responsiveness and association with insulin action in older adults. Using an integrated workflow combining centrifugation, polymer-based precipitation, and single-EV sorting, we isolated RYR1+ and RYR- EVs secreted from myobundles-3D contractile skeletal muscle tissues engineered from primary muscle progenitor cells obtained from healthy donors (n = 6). We also isolated plasma EVs from 48 human participants and performed targeted high-resolution flow cytometry to evaluate EV biomarkers associated with aging, insulin action, and exercise responsiveness in older adults.
RESULTS: By smRNA sequencing, compared to myobundle RYR- EVs, RYR1+ EVs contained three unique microRNAs (miRNAs) and an additional 21 miRNAs with significantly greater abundance (including canonical myoMiRs miR-206, miR-1-3p, and miR-208a-3p). Of the 24 RYR1+ EV-enriched miRNAs, experimentally-supported mRNA targets (n = 422) are involved in pathways governing cell proliferation, apoptosis, senescence, insulin and glucose signaling. In two independent cohorts, including older adults with prediabetes or unknown prediabetes status, frequencies of RYR1+ EV subsets were significantly upregulated by chronic exercise with greater RYR1+ EV frequencies associated with better insulin action.
CONCLUSIONS: These complementary in vitro and in vivo data identify skeletal muscle-derived RYR1+ EVs as upregulated by exercise and as carriers of miRNAs linked to insulin action in older adults, including those with prediabetes. These results highlight skeletal muscle-derived EVs as novel biomarkers and potential mediators of systemic metabolic regulation and healthy aging.

Keywords:  Exercise; Extracellular vesicles; HOMA-IR; Insulin; MiRNA; Single vesicle sorting; Skeletal muscle; piRNA

DOI:  https://doi.org/10.1186/s12967-026-08215-w
Proc Natl Acad Sci U S A. 2026 Jun 02. 123(22): e2605194123

Perturbation of RNA homeostasis impairs mitochondrial respiration during poxvirus infection through excess RNA accumulation.

Djamal Brahim Belhaouari, Anil Pant, Santiago Navarro-Forero, Fernando Cantu, Zhilong Yang.

  Induction of RNA degradation in infected cells is a strategy used by many viruses to promote efficient replication. Vaccinia virus, the prototype poxvirus and the vaccine platform for smallpox and mpox, encodes two decapping enzymes to accelerate mRNA and double-stranded RNA (dsRNA) degradation during infection, through functional coordination with host cell RNA exonuclease. Previous studies have largely focused on RNA degradation as a mechanism for regulating viral gene expression and evading innate immune sensing. Here, we show that impaired RNA degradation in vaccinia virus-infected cells, due to either depletion of viral decapping enzymes or cellular exonuclease, severely compromises mitochondrial respiration and integrity. We further demonstrated that accumulation of excess dsRNA and mRNA, including pseudouridine-modified RNAs, is sufficient to induce profound defects in mitochondrial respiration and integrity. Notably, this impairment occurs independently of interferon induction and dsRNA innate immune sensor Protein Kinase R. Moreover, excess RNA suppresses respiration in purified cell-free mitochondria and physically associates with mitochondria in cell-free and cellular contexts, supporting an immune-independent mechanism. Excess mRNA and dsRNA reduce mitochondrial membrane potential in both cells and purified mitochondria, indicating disruption of the proton gradient as the mechanism underlying impaired mitochondrial respiration and integrity. Together, these findings identify excess mRNA and dsRNA as perturbants of mitochondrial homeostasis in cells with dysfunctional RNA degradation during vaccinia virus infection, revealing a paradigm-shift concept linking RNA metabolism to mitochondrial function. The finding carries broad implications for understanding RNA and mitochondrial biology and RNA-based therapeutics and vaccines.

Keywords:  RNA degradation; dsRNA; mRNA; mitochondrial respiration; poxvirus

DOI:  https://doi.org/10.1073/pnas.2605194123
Int J Mol Sci. 2026 May 08. pii: 4197. [Epub ahead of print]27(10):

Single-Cell Proteomics Decodes the Cellular Response to Lysosomal Storage in C. elegans Coelomocytes.

Yiming Lei, Fanghua Lu, Qinqin Xu, Lishuan Wu, Qun Fang, Hongyun Tang.

  Lysosomal storage, characterized by the progressive accumulation of undigested substrates in the lysosomal lumen, is a primary driver of various lysosome-related diseases. However, single-cell proteomic remodeling during lysosomal storage remains elusive, and the cellular responses for coping with this condition are poorly understood. Here, we employed deep-coverage single-cell proteomics to analyze C. elegans scavenger cells (coelomocytes) undergoing lysosomal storage. Our analysis revealed profound proteomic remodeling characterized by the massive, asymmetric upregulation of nearly 1000 proteins. We identified a coordinated compensatory response involving the robust induction of endoplasmic reticulum (ER) quality control, including ER unfolded protein response and ER-associated degradation, systemic hyperactivation of the ubiquitin-proteasome system (UPS), and a discordant mitochondrial response featuring concurrent bioenergetic upregulation and severe proteostatic stress. Collectively, this single-cell analysis establishes a high-resolution molecular blueprint of the hierarchical strategies cells employ to survive lysosomal collapse via compensatory quality control mechanisms.

Keywords:  Caenorhabditis elegans; cellular stress response; lysosomal storage; proteostasis; single-cell proteomics

DOI:  https://doi.org/10.3390/ijms27104197
Expert Opin Ther Targets. 2026 May 29.

RNA-centric approaches in amyotrophic lateral sclerosis: prospects for future therapeutics.

Valentina La Cognata, Giulia Gentile, Giovanna Morello, Maria Guarnaccia, Sebastiano Cavallaro.

   INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by profound clinical and molecular heterogeneity, which has substantially hindered the development of effective therapies. Significant advances in ALS research have been driven by the study of RNA biology, together with the implementation of advanced transcriptomic technologies and artificial intelligence - based algorithms, which are assuming a transformative role in reshaping the field.
AREAS COVERED: We discuss how genome-wide expression profiling enables the identification of molecular signatures for drug discovery and repurposing, facilitates the stratification of patients into biologically distinct subtypes for more refined clinical trials, and guides the development of novel nucleic acid-based therapies. Furthermore, we explore the potential of transcriptomics to identify molecular vulnerabilities during pre-symptomatic stages, paving the way for early intervention.
EXPERT OPINION: The convergence of transcriptomics and artificial intelligence is poised to fundamentally redefine ALS, transforming it from a single clinical entity into a spectrum of molecularly defined disorders, each potentially amenable to targeted therapeutic intervention. While challenges in translating high-dimensional data into clinical practice remain, the integration of transcriptomics with advanced computational tools promises to accelerate the transition toward a new era of personalized medicine in ALS.

Keywords:  AI; ASO; Amyotrophic lateral sclerosis; RNA; drug discovery; drug repurposing; early intervention; patient stratification; transcriptomics

DOI:  https://doi.org/10.1080/14728222.2026.2682782