bims-musmir 2026-02-08 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–02–08
nineteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
Largely Distinct Post-Translational Modifications Differentiate Skeletal Muscle Wasting Caused by Cancer, Dexamethasone and Aging.
Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.
MicroRNA Regulatory Targets Related to VO 2 peak Decline in Older Adult Participants of the Study of Muscle, Mobility and Aging (SOMMA).
Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.
Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons.
Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15.
Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.
Association of mitochondrial oxidative capacity with physical fitness in ageing: the Baltimore longitudinal study of ageing.
Butyrate extends health and lifespan in mice with mitochondrial deficiency.
Leveraging mitochondrial stress to improve healthy aging.
Maternal slow-release nitrogen diets during late gestation optimize the energy metabolism in calves' skeletal muscle.
Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions.
In silico transcriptome-based drug screening identifies celastrol as a multi-species therapeutic agent against aging-related sarcopenia and mitochondrial dysfunction.
Serum metabolomic signatures associated with frailty-related phenotypes in a cohort of older people.
Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease.
BMAL1 downregulation exacerbates age-related nonalcoholic steatohepatitis by promoting NLRP3 inflammasome activation via HIF-1ɑ-mediated glycolysis.
Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes.
Obesity Reprogrammes Adipose Extracellular Vesicles to Induce Muscle Atrophy via miR-150-5p-Mediated Transcriptional Silencing.

bioRxiv. 2026 Jan 14. pii: 2026.01.13.699119. [Epub ahead of print]

Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.

Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.

Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced aged, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in (i) aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control, and (ii) in human primary myotubes. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. In the cell model, ROS and glutathione was measured using luminescent assays. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. In the cell model, B12 supplementation reduced ROS levels. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

DOI: https://doi.org/10.64898/2026.01.13.699119
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70220

Largely Distinct Post-Translational Modifications Differentiate Skeletal Muscle Wasting Caused by Cancer, Dexamethasone and Aging.

Anna Stephan, Flavia A Graca, Suresh Poudel, Yingxue Fu, Yong-Dong Wang, Myriam Labelle, Fabio Demontis.

   BACKGROUND: Skeletal muscle wasting and weakness are prominent disease features. Originally considered to arise from common transcriptional changes, recent analyses demonstrated that different stimuli induce muscle wasting via largely distinct mRNA and protein changes.
METHODS: Here, we examined the post-translational modifications (PTMs) associated with muscle wasting induced by cancer (n = 15 078), dexamethasone (n = 15 078) and aging (n = 8777) in mice by utilising the JUMPptm pipeline to recover modified peptides from TMT (tandem mass tag) mass spectrometry analyses.
RESULTS: We find that most PTMs that are significantly regulated are stimulus-specific and that only a few are cross-shared (n = 10; p < 0.05). These include P27 dihydroxylation of Lrpprc (leucine-rich pentatricopeptide repeat containing), an RNA binding protein and transcriptional co-activator mutated in Leigh syndrome, a mitochondrial disease. Contrary to the stimulus-specificity of other atrophy-associated PTMs, P27 dihydroxylation of Lrpprc declines (~20%; p < 0.05) with muscle wasting irrespective of the atrophic trigger. Electroporation of dihydroxylation-resistant LrpprcP27A (which mimics the reduction in Lrpprc dihydroxylation that occurs with atrophy) reduces muscle force in young (~23%-39%; p < 0.01) and old (~26%-36%; p < 0.01) male mice compared to the contralateral electroporation of LrpprcWT, indicating that a decline in Lrpprc P27 dihydroxylation contributes to muscle weakness in response to diverse catabolic stimuli. Comparison of LrpprcWT versus GFP electroporation indicates that there are mostly non-significant effects (p > 0.05) on muscle force in young and old mice. Mechanistically, LrpprcP27A does not affect proteostasis and mitochondrial function compared to control LrpprcWT but impairs (> 60% decline; p < 0.05) the expression of genes necessary for muscle strength, including the apelin receptor Aplnr and Col6a2/6 collagens. Moreover, LrpprcP27A reduces type 2b myofibre size (13% decline; p < 0.01) in old but not in young age.
CONCLUSIONS: These analyses identify atrophy-associated PTMs that provide refined biomarkers for fingerprinting the atrophic stimulus. Although most PTMs are stimulus-specific, P27 dihydroxylation of Lrpprc declines during muscle wasting induced by cancer, dexamethasone and aging, suggesting that this is a general atrophy marker. Experimental up-regulation of the atrophy-mimicking variant LrpprcP27A reduces muscle force compared to wild-type Lrpprc in young and old mice, suggesting that atrophy-associated P27 dihydroxylation contributes to disease-associated muscle weakness.

Keywords:  Leigh syndrome; Lrpprc; aging; atrophy; cancer cachexia; post‐translational modifications; sarcopenia; skeletal muscle weakness

DOI:  https://doi.org/10.1002/jcsm.70220
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70214

Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.

Mia Y Kawaida, Abigail L Tice, Samuel Alvarez, Jacob A Lackey, Benjamin Izaguirre, Qingping Yang, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan.

   BACKGROUND: L-Kynurenine (L-Kyn), a product of tryptophan catabolism, increases with age and has been associated with reduced physical function and increased frailty in humans. Robustly expressed in skeletal muscle, kynurenine aminotransferases (KATs) degrade L-Kyn into kynurenic acid and are regulated by the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α).
METHODS: The study investigated (1) if elevating L-Kyn levels via a diet intervention exacerbates an age-related decline in physical, muscle and mitochondrial functions and (2) if transgenic expression of PGC1α in skeletal muscle (MCK-PGC1α) protects against age-dependent L-Kyn associated pathology in a cohort of aging MCK-PGC1α transgenic mice and their wildtype littermates of both sexes (n = 262). Physical function was assessed longitudinally from 16 to 24 months of age using treadmill endurance capacity, grip strength, walking speed and daily physical activity. Muscle function was assessed in situ using nerve-mediated contraction of the soleus muscle. Mitochondrial energetics were assessed using high resolution respirometry and fluorescence spectroscopy.
RESULTS: MCK-PGC1α transgenic mice had significantly higher KAT expression ~2-5-fold compared with wildtype littermates (p < 0.0001 for all isoforms). A main effect of L-Kyn diet was observed for decreasing treadmill endurance capacity and daily physical activity in male mice (p ≦ 0.002). A main effect of L-Kyn diet for decreasing maximal walking speed only was found in female mice (p = 0.037). Correspondingly, L-Kyn increased frailty prevalence in male (+17%) and female (+26%) wildtype mice (p = 0.025 and 0.0001 respectively), which was mitigated by MCK-PGC1α in both sexes. Soleus muscle strength and power were not impacted by diet or genotype in either sex (p > 0.5). Mitochondrial oxidative phosphorylation function in male and female MCK-PGC1α mice was greater than wild type mice regardless of diet (p < 0.04), which is likely driven by upregulated expression of mitochondrial biogenesis related genes.
CONCLUSIONS: We conclude that PGC1α overexpression in skeletal muscle mitigates the exacerbation of physical frailty induced by elevated circulating L-Kyn in aging mice, in part through increased skeletal muscle capacity for L-Kyn metabolism due to PGC1α-induced increase in muscle KAT expression.

Keywords:  aging; frailty; mitochondria; muscle; physical function

DOI:  https://doi.org/10.1002/jcsm.70214
bioRxiv. 2026 Jan 22. pii: 2026.01.19.700188. [Epub ahead of print]

MicroRNA Regulatory Targets Related to VO 2 peak Decline in Older Adult Participants of the Study of Muscle, Mobility and Aging (SOMMA).

Genesio M Karere, Fang-Chi Hsu, Russell T Hepple, Paul M Coen, Steve R Cummings, Anne B Newman, Nancy W Glynn, Lauren M Sparks, Nancy E Lane, Albert G Hayward, Jianzhao Xu, Nathan Wagner, Ge Li, Jeanne Chan, Laura A Cox, Stephen B Kritchevsky.

Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA-gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70-79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA-gene interactions to uncover therapeutic targets for preserving muscle function with age.

DOI: https://doi.org/10.64898/2026.01.19.700188
FASEB Bioadv. 2026 Feb;8(2): e70088

Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice.

Takanaga Shirai, Hideto Hanakita, Kohei Takeda, Yu Kitaoka, Kaori Ishikawa, Kazuto Nakada, Tohru Takemasa.

  Mitochondrial function is essential for skeletal muscle health, and its disruption leads to atrophy and functional decline. This study examines the impact of denervation on skeletal muscle mitochondria in polymerase gamma (PolG)(+/mut) mice, which accumulate mitochondrial DNA (mtDNA) mutations due to a partial deficiency in polymerase gamma proofreading. Using a 14-day denervation protocol, we assessed muscle mass, mtDNA copy number, oxidative stress and mitochondrial dynamics in wild-type (WT) and PolG(+/mut) mice. Our findings reveal that while denervation significantly reduced muscle wet weight and mitochondrial enzyme activity, no genotype-specific differences in muscle atrophy were observed. However, PolG(+/mut) mice displayed more disorganized mitochondrial cristae and elevated oxidative stress markers, indicating greater mitochondrial vulnerability. Despite these changes, the lack of significant differences in mitochondrial proteins and gene expression between genotypes may reflect an adaptive antioxidant response, including increased catalase expression, although the compensatory nature of this response cannot be conclusively determined. These results suggest that oxidative stress-related responses are involved in mitochondrial adaptations during denervation-induced muscle atrophy. The increased expression of antioxidant enzymes, such as catalase, in PolG(+/mut) mice suggests that antioxidant mechanisms are activated in response to increased oxidative stress. These findings underscore the importance of controlling oxidative stress for maintaining muscle health.

Keywords:  atrophy; mitochondria; mtDNA; oxidative stress; polymerase gamma; skeletal muscle

DOI:  https://doi.org/10.1096/fba.2025-00072
Brain. 2026 Feb 06. pii: awag045. [Epub ahead of print]

Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons.

Jordan Mecca, Julien Mignot, Marianne Gervais, Teoman Ozturk, Stéphanie Astord, Juliette Berthier, Stéphanie Bauché, Julien Messéant, Maria G Biferi, Hélène Rouard, Martine Barkats, Frédéric Relaix, Nathalie Didier.

  Spinal Muscular Atrophy (SMA) is due to a deficit in SMN, a ubiquitously expressed protein encoded by the Survival of Motor Neuron 1 (SMN1) gene. Recently, SMN-targeted disease modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. Skeletal muscle tissue and the Muscle Stem Cells (MuSC) that sustain its postnatal growth and regenerative capacity, are affected by SMN deficit. While a direct contribution of muscle tissue in the disease progression has been demonstrated, the extent to which MuSC are involved in this process remains to be established. Using SMA type II patient muscle biopsies and several mutant mouse models, we performed an accurate study of SMN role in MuSC function during postnatal growth and adulthood. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ MuSC. In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth, and that SMN deficit compromises MuSC reservoir establishment. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that deletion of a single Smn allele is sufficient to induce quiescent MuSC apoptosis in adult muscle, showing that high levels of SMN are required for the maintenance of the quiescent MuSC reservoir. We further established that depletion of MuSC yielded neuromuscular junctions remodeling followed by a non-cell autonomous loss of part of the alpha motor neurons (MN) in the long term. Overall, our findings demonstrate an interdependence between quiescent MuSC and the MN reservoirs, supporting that MuSC may be important therapeutic targets for the long-term treatment of SMA. Moreover, we provide important insights into the specific SMN requirements of MuSC, which could be valuable for to the development of next generation combinatorial therapies.

Keywords:  motor neurons; muscle stem cells; neuromuscular junctions; spinal muscular atrophy

DOI:  https://doi.org/10.1093/brain/awag045
Nat Commun. 2026 Jan 30.

Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15.

Jinhai Yu, Tong Guo, Arun Gupta, Ernesto M Llano, Thomas Salisbury, Naureen Wajahat, Dianne Zhao, Sean Slater, Qing Deng, Esra A Akbay, Beverly A Rothermel, John M Shelton, Bret M Evers, Zhidan Wu, Iphigenia Tzameli, Evanthia Pashos, James Kim, John D Minna, Puneeth Iyengar, Rodney E Infante.

Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implicate tumor-derived GDF15 as a key mediator and therapeutic target in STK11/LKB1-mutant NSCLC-associated cachexia.

DOI: https://doi.org/10.1038/s41467-026-68702-y
J Physiol. 2026 Feb 03.

Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.

Andrea Telek, Ivett Gabriella Szabó, Anikó Keller-Pintér, Mónika Gönczi, Eliza Guti, László Szabó, Brigitta Tillmann, Zoltán Márton Kohler, László Juhász, Péter Bai, Szilárd Póliska, Zsuzsanna Gaál, László Csernoch, János Fodor.

  Mitochondria are dynamic organelles that undergo fusion and fission. Key proteins are needed to create mitochondrial networks, as well as facilitate biogenesis, fragmentation or movement within the cell. Septins are considered as the fourth component of the cytoskeleton, providing attachment sites for proteins. Besides that, they have important roles in different cellular processes, including mitochondrial fission and fusion (remodelling). Septins form oligomeric complexes comprising various septin subgroups, which can create higher-order structures. Septin7 is the sole member of its subgroup. We aimed to examine how mitochondrial dynamics and oxidative phosphorylation (OXPHOS) are affected in Septin7 downregulated C2C12 (S7-KD) myoblasts and terminally differentiated myotubes compared to scrambled short hairpin RNA-transfected control cells. We detected altered expression of genes related to mitochondrial biogenesis (PGC1α), dynamics (DRP1, OPA1 and MFN2) and autophagy (PINK1 and BNIP3); furthermore, a significant decrease in differentiation-dependent mRNA expression of OXPHOS markers (ATP synthase, COX1 and SDH). Septin7 downregulation also affected the expression of post-translational modifications of MFN2 and DRP1. Functional measurements of OXPHOS revealed decreased O2 consumption (flux) and higher O2 concentration in Septin7 KD cultures following selective inhibition of electron transport complexes. We observed significant alterations in basal respiration and OXPHOS pathways in Septin7 KD cultures. Our results suggest that Septin7, as a cytoskeletal protein, could be a significant regulator of mitochondrial dynamics and oxidative metabolism. Therefore, these molecules, as mitochondrial dynamics modulators, can serve as potential therapeutic targets in diseases related to changes in mitochondrial function. KEY POINTS: Knockdown of Septin7 results in altered gene and protein expression of markers controlling mitochondrial dynamics. Diminished level of Septin7 causes decreased gene expression of members of oxidative phosphorylation. Knockdown of Septin7 has an impact on microRNAs involved in the regulation of mitochondrial markers. Septin7 has an impact on mitochondrial respiration.

Keywords:  electron transport; mitochondria; remodelling; septin; skeletal muscle

DOI:  https://doi.org/10.1113/JP288715
Age Ageing. 2026 Feb 01. pii: afag022. [Epub ahead of print]55(2):

Association of mitochondrial oxidative capacity with physical fitness in ageing: the Baltimore longitudinal study of ageing.

Caterina Trevisan, Qu Tian, Kenneth W Fishbein, Sarah Church, Eleanor M Simonsick, Josephine M Egan, Stefano Volpato, Luigi Ferrucci.

   BACKGROUND: In younger individuals, fitness is mostly influenced by muscle mitochondrial oxidative phosphorylation (OxPhos) and cardiac output. However, compared with younger individuals, various impairments may also negatively affect fitness in older adults.
OBJECTIVE: To investigate the relationship of OxPhos with cardiorespiratory fitness, the energetic cost of walking and aerobic resilience with respect to age.
DESIGN: Cross-sectional.
SETTING: Population.
SUBJECTS: Six hundred and forty-nine Baltimore longitudinal study of ageing participants (mean age 64.5 years, 56.9% females).
METHODS: Muscle mitochondrial OxPhos was measured as phosphocreatine recovery rate (kPCr) through 31P magnetic resonance spectroscopy. Based on age- and sex-specific kPCr z-scores, we classified individuals with low (≤ -0.5 standard deviations [SD]), average (-0.5 to 0.5SD) and high (>0.5SD) OxPhos. Cardiorespiratory fitness was measured as peak oxygen consumption (MVO2 peak) during a treadmill testing. The energetic cost of usual pace walking was expressed as the average oxygen consumption per 100 metres. Aerobic resilience was the ratio between MVO2 peak and average VO2 during usual pace walking.
RESULTS: Participants with higher kPCr had 4.07 (95%CI: 2.88, 5.26) ml/kg/min higher MVO2 peak and 0.19 (95%CI: 0.06, 0.32) higher aerobic resilience than those with lower kPCr. The energetic cost of walking was greater by 0.84 (95% CI: 0.21, 1.47) ml/kg/100 m in those with high than low kPCr. A multiplicative interaction between age and kPCr was identified in the regressions predicting MVO2 peak and aerobic resilience (pinteraction = 0.01), with differences between OxPhos groups attenuating after age 70.
CONCLUSION: Muscle mitochondrial OxPhos contributes to interindividual variability in cardiorespiratory fitness, especially in young and middle adulthood.

Keywords:  ageing; cohort study; energetic cost of walking; mitochondria; older people; physical fitness

DOI:  https://doi.org/10.1093/ageing/afag022
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699287. [Epub ahead of print]

Butyrate extends health and lifespan in mice with mitochondrial deficiency.

Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.

Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfam fl/fl Ub Cre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.

DOI: https://doi.org/10.64898/2026.01.13.699287
Sports Med Health Sci. 2026 Jan;8(1): 23-33

Leveraging mitochondrial stress to improve healthy aging.

Abril Gorgori-Gonzalez, Silvana Soto-Rodriguez, Eva Tamayo-Torres, Esther Garcia-Dominguez, Vicente Sebastia, Juan Gambini, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera.

  Aging is characterized by a progressive decline in physiological function, driven by intrinsic mechanisms (primary aging) and modifiable factors (secondary aging), ultimately leading to multimorbidity, disability, and mortality. Mitochondrial dysfunction, a major hallmark of aging, plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia. With age, mitochondrial quality control processes, including biogenesis, mitophagy, and dynamics, become dysregulated, impairing energy metabolism and muscle homeostasis. Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty, such as the decrease in walking speed and muscle strength, making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity. Mitohormetic agents induce reversible mitochondrial stress, triggering adaptive responses that enhance function. Among these interventions, physical exercise, particularly endurance and resistance training (RT), has been reported to be among the most effective, as it may modulate mitochondrial biogenesis, dynamics, and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) expression, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and mitochondrial content. Chronic RT can also elevate fusion and fission markers, potentially as a compensatory mechanism to mitigate mitochondrial damage. Apart from exercise, mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field. By modulating mitochondrial bioenergetics and dynamics, they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.

Keywords:  Frailty; Mitochondrial dysfunction; Mitohormesis; Muscle homeostasis; Phytochemicals; Resistance training

DOI:  https://doi.org/10.1016/j.smhs.2025.10.003
PLoS One. 2026 ;21(1): e0338860

Maternal slow-release nitrogen diets during late gestation optimize the energy metabolism in calves' skeletal muscle.

Thaís Correia Costa, Diana Carolina Cediel-Devia, Germán Darío Ramirez-Zamudio, Karolina Batista Nascimento, Mateus Pies Gionbelli, Marcio de Souza Duarte.

The current study aimed to determine the enriched biological process, through proteomic and transcriptome data, associated with maternal slow-release nitrogen diets received during late gestation on the skeletal muscle of the offspring. At day 180 to day 268 of gestation a total of 16 pregnant Brahman cows, were assigned into Control treatment (CON; n = 7), where cows were fed ad libitum a low crude protein basal diet plus mineral mixture; or Slow-released nitrogen (SRN, n = 9) based diet, where cows were fed a basal diet plus a slow-release nitrogen supplement. Muscle biopsy was performed at day 45 of age in calves and used to perform RNA sequencing (RNA-seq) and proteomic (HPLC-MS/MS) analyses. Although the experimental treatment did not show effects on transcript abundance, proteomic analysis revealed significant differences in protein expression. Enriched (adjusted p-value ≤ 0.05) biological processes from the exclusive proteins identified in calves' skeletal muscle from SRN group are related to central energy metabolism (synthesis of Acetyl-CoA, tricarboxylic acid cycle, isocitrate metabolic process), regulation of calcium and nitrogen transport, and protein folding. Protein-protein interaction network assessed in the differentially abundant proteins (DAPs) revealed 4 main enriched biological processes, including ATP metabolic process, glucose metabolism, tricarboxylic acid cycle, and sarcomere organization. These findings suggest that maternal supplementation whit slow-release nitrogen during late gestation can positively influence postnatal energy metabolism in calf skeletal muscle.

DOI: https://doi.org/10.1371/journal.pone.0338860
Nat Aging. 2026 Feb 03.

Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions.

Christian Gallrein, David H Meyer, Yvonne Woitzat, Valeria Ramirez-Ramirez, Thanh Vuong-Brender, Janine Kirstein, Björn Schumacher.

Different neuron types show distinct susceptibility to age-dependent degeneration, yet the underlying mechanisms are poorly understood. Here we applied aging clocks to single neuron types in Caenorhabditis elegans and found that distinct neurons differ in their biological age. Ciliated sensory neurons with high neuropeptide and protein biosynthesis gene expression show accelerated aging and degeneration, correlating with loss of function, which could be prevented by pharmacological inhibition of translation. We show that the C. elegans neuronal aging transcriptomes correlate with human brain aging patterns and anticorrelate with geroprotective interventions. We performed an in silico drug screen to identify potentially neuroprotective small molecules. We show that the natural occurring plant metabolite syringic acid and the piperazine derivative vanoxerine delay neuronal degeneration, and propose these compounds as neuroprotective interventions. Furthermore, we identify neurotoxins that accelerate neurodegeneration, indicating that distinguishing aging trajectories between neuron types can inform on protective interventions as well as risk factors.

DOI: https://doi.org/10.1038/s43587-026-01067-5
J Adv Res. 2026 Feb 03. pii: S2090-1232(26)00107-4. [Epub ahead of print]

In silico transcriptome-based drug screening identifies celastrol as a multi-species therapeutic agent against aging-related sarcopenia and mitochondrial dysfunction.

Bangfu Wu, Jiaxin Liu, Zhaoyu Cui, Xingzhu Yin, Li Mo, Li Chen, Huimin Chen, Xuer Cheng, Yu Wang, Fangqu Liu, Chanhua Liang, Yuna Tian, Yuxia Chen, Xiaocui Liu, Yanyan Li, Ping Yao, Chao Gao, Yuhan Tang.

   INTRODUCTION: Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.
OBJECTIVES: This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction.
METHODS: We analyzed age-stratified muscle transcriptome datafrom various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. In silico transcriptome-based drug screening was conducted using the Connectivity Map (CMap). Subsequently, C2C12 myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction. Celastrol's efficacy and mechanisms were assessed through histological analysis, molecular biology, and transcriptomics analysis.
RESULTS: Celastrol, a bioactive triterpenoid from Tripterygium wilfordii Hook. F., was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6% at 10 μM, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.
CONCLUSION: Collectively, these findings suggest celastrol as apharmacological mimetic of exercise-induced mitochondrial rejuvenation, offering a translatable strategy to combat age-related muscle decline.

Keywords:  CMap; Celastrol; Mitochondria; Myogenic differentiation; PGC-1α; Sarcopenia

DOI:  https://doi.org/10.1016/j.jare.2026.01.079
Geroscience. 2026 Jan 31.

Serum metabolomic signatures associated with frailty-related phenotypes in a cohort of older people.

Céline Bougel, Rémi Servien, Nathalie Vialaneix, Elise Maigne, Yves Boirie, Clément Lahaye, Cécile Canlet, Laurent Debrauwer, Valentin Max Vetter, Kristina Norman, Dominique Dardevet, Ilja Demuth, Sergio Polakof.

  Frailty is a geriatric syndrome characterized by reduced physiological reserves and increased vulnerability to stressors. Given its complex phenotypes and underlying biology, robust multidimensional biomarkers are needed to advance personalized care. We aimed to identify serum metabolomics signatures associated with frailty phenotypes and related features. We analyzed serum metabolomics data in 901 participants (47.5% males, mean age 68.3 ± 3.5 years) from the Berlin Aging Study II, classified as non-frail, pre-frail, or frail using Fried's criteria at baseline (T0) and after 7 years (T1). Linear models assessed associations between metabolite levels, frailty, and related parameters. At T0, 1% were frail, increasing to 4.8% at T1. Over follow-up, 323 participants transitioned to a worse frailty category. Across 82 metabolites, no significant differences emerged for frailty status. However, in males, 27 and 30 circulating metabolites were negatively associated with handgrip strength at T0 and T1, respectively. Also in males, L-tyrosine was positively associated with fat mass, while 22 metabolites (carbohydrate-related, maltose, fructose, glucose, galactitol, mannose, lactate, acetylcarnitine; amino acid-related, valine, tyrosine, isoleucine, α-hydroxybutyrate) correlated with nutritional status at T0. In females, dimethylsulfone was positively associated with changes in handgrip strength over time, and glycerol with appendicular lean mass at T0. While serum metabolomics showed weak associations with frailty itself, clear links were observed with frailty-related features, notably muscle strength and nutritional status. These findings highlight insulin sensitivity as a central determinant, suggesting that early metabolic alterations may contribute to impaired muscle health in aging.

Keywords:  Amino acid metabolism; Biomarkers; Insulin sensitivity; Metabolite; Metabolomics; Prevention

DOI:  https://doi.org/10.1007/s11357-026-02116-y
Free Radic Biol Med. 2026 Jan 29. pii: S0891-5849(26)00073-0. [Epub ahead of print]

Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease.

Yingqi Xu, Junyu Li, Shanshan Ma, Ting Yang, Ziyue Shen, Mingtao Li, Qiaoying Huang.

  Extrusion of damaged mitochondria is emerging as a trigger of innate immune activation. Parkinson's disease (PD), characterized by profound mitochondrial dysfunction, may involve similar mechanisms. Here, we report that dopaminergic neurons release damaged mitochondria into the extracellular space in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. These neuron-derived mitochondria were subsequently engulfed by glial cells, eliciting robust inflammatory responses. Autophagy inhibition did not affect mitochondrial release, indicating a non-canonical extrusion pathway. Upon mitochondrial damage, Rab27a and Rab27b translocated to the outer mitochondrial membrane, mediating mitochondrial export from dopaminergic neurons. Conditional Rab27 knockdown in dopaminergic neurons reduced extracellular mitochondrial accumulation, microglial activation, antiviral signaling, and dopaminergic neurodegeneration. Together, these findings identify Rab27-dependent mitochondrial extrusion as a critical mechanism coupling dopaminergic neuronal injury to neuroinflammation and neurodegeneration in PD.

Keywords:  Parkinson's disease; Rab27; dopaminergic neurons; mitochondria; neuroinflammation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.053
Free Radic Biol Med. 2026 Jan 30. pii: S0891-5849(26)00078-X. [Epub ahead of print]246 562-579

BMAL1 downregulation exacerbates age-related nonalcoholic steatohepatitis by promoting NLRP3 inflammasome activation via HIF-1ɑ-mediated glycolysis.

Yujie Ren, Dongying Lv, Jiayan Chen, Wenjing Chen, Chu Chen, Lizong Zhang, Jue Tu, Keyan Zhu, Dejun Wang, Zhaowei Cai.

   INTRODUCTION: Epidemiological studies have demonstrated higher incidence and mortality rate of nonalcoholic steatohepatitis (NASH) in the elderly population than in younger groups. However, the mechanisms underlying this age-related exacerbation remain poorly understood.
OBJECTIVE: This study aimed to elucidate the specific pathways through which aging exacerbates NASH progression, using an integrated in vivo and in vitro model.
METHODS: Aged (18-month-old) and young (6-week-old) mice were fed a high-fat diet (HFD) for 16 weeks to induce NASH. A senescence-associated cellular model of NASH was established by co-treating murine hepatocyte AML-12 with H2O2 and free fatty acid (FFA). Gene expression profiling of liver tissue was performed using RNA sequencing to identify molecular signatures. Interventions were as follows: (1) In vitro, BMAL1 overexpression plasmids were transfected into AML-12 cells, followed by treatment with 2-deoxy-D-glucose (2-DG, a glycolysis inhibitor) and 2-methoxyestradiol (2-ME2, a HIF-1α inhibitor); (2) in vivo, hepatocyte-specific BMAL1 overexpression was achieved in aged HFD-fed mice through adeno-associated virus serotype 8 (AAV8) delivery. Mechanism validation was performed using biochemical assays, Western blot, cell staining, molecular docking, and Co-IP.
RESULTS: Aged HFD-fed mice exhibited more severe NASH phenotypes than young mice. Transcriptomic analysis identified NLRP3-related signaling and circadian rhythm pathways as central contributors to age-specific NASH pathogenesis. These mice also exhibited elevated NLRP3 inflammasome activity, enhanced glycolysis, and reduced BMAL1 expression. In senescent NASH cells, BMAL1 overexpression along with 2-DG or 2-ME2 treatment significantly downregulated NLRP3 expression and attenuated lipid accumulation, inflammation, oxidative stress, and fibrosis. Mechanistically, BMAL1 directly bound to HIF-1α, thereby suppressing glycolysis. Hepatocyte-specific BMAL1 overexpression in aged HFD-fed mice markedly inhibited glycolysis and NLRP3 activation, resulting in an improvement in NASH-related pathologies.
CONCLUSION: This study revealed a novel mechanism in which BMAL1 downregulation under aging and HFD conditions promotes NASH progression by binding to HIF-1α and modulating the glycolysis-NLRP3 inflammasome axis.

Keywords:  Aging; BMAL1; Glycolysis; NLRP3 inflammasome; Nonalcoholic steatohepatitis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.058
Science. 2026 Feb 05. 391(6785): eadv2600

Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes.

Xin Jiang, Laure Schaeffer, Divya Patni, Tommaso Russo, Chao-Zong Lee, Corey Aguilar, Christine Marques, Karen Jansen-West, Marian Hruska-Plochan, Ananya Ray-Soni, Su Min Lim, Aaron Held, Mei Yue, Paula Castellanos Otero, Sandeep Aryal, Hortense D A M Beaussant, Himanish Basu, Hiro Takakuwa, Lillian M Daughrity, Nandini Ramesh, Paulo Da Costa, Ana Rita A A Quadros, Matthew Nolan, Charles Jourdan F Reyes, Hayden Wheeler, Laura C Moran, Grant Griesman, Benjamin Wymann, Bianca A Trombetta, Emma Sofia Lopez-De-Silanes, Michael Canori, Gopinath Krishnan, Yasmim Vieira Souza Da Silva, Gilbert Eriani, Mark W Albers, Steven E Arnold, Yuyu Song, Ankur Jain, Isaac M Chiu, Yong-Jie Zhang, Fen-Biao Gao, Brian J Wainger, Magdalini Polymenidou, Leonard Petrucelli, Franck Martin, Clotilde Lagier-Tourenne.

GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell-derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.

DOI: https://doi.org/10.1126/science.adv2600
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70204

Obesity Reprogrammes Adipose Extracellular Vesicles to Induce Muscle Atrophy via miR-150-5p-Mediated Transcriptional Silencing.

Joshua M J Price, Michael Macleod, Thomas Nicholson, Caitlin M Ditchfield, Bethy Airstone, Natalie Lachlan-Jiraskova, Edward T Davis, Kostas Tsintzas, Simon W Jones.

   BACKGROUND: Sarcopenic obesity, where excess body fat coexists with reduced muscle mass and function, is becoming increasingly common in ageing populations and contributes to poor physical and metabolic health. Although adipose tissue-secreted factors are implicated in muscle decline, the specific mechanisms remain unclear. Extracellular vesicles (EVs), which carry regulatory cargo such as microRNAs (miRNAs) between cells, may play a key role in this adipose-muscle communication.
METHODS: EVs were isolated from adipose-conditioned media (ACM) collected from lean and non-lean human donors using ultracentrifugation. Donors were grouped by BMI (lean: 20.7-24.4; non-lean: 25.3-39.3) and age (younger: 31-56 years; older: 60-84 years). EVs were characterised using nanoparticle tracking analysis (NTA), ExoView, nanoscale flow cytometry (CytoFLEX Nano) and transmission electron microscopy (TEM). Primary human myoblasts were differentiated into myotubes and treated for 24 h with lean or non-lean EVs (1.3 × 109 particles/mL) or left untreated. Myotube thickness was measured by immunofluorescence microscopy. Transcriptomic changes were assessed by bulk RNA sequencing. EV miRNA cargo was profiled by small RNA-seq and validated by qPCR. The role of miR-150-5p was tested using antagomir inhibition.
RESULTS: Non-lean EVs significantly reduced myotube thickness in older adult-derived myotubes compared to both untreated controls (8.7 ± 1.66 μm vs. 12.4 ± 1.72 μm, p < 0.01) and lean EV-treated myotubes (8.7 ± 1.66 μm vs. 13.2 ± 3.84 μm, p < 0.05), indicating a donor BMI-specific effect. This atrophy was restricted to myotubes derived from older donors. The same experimental approach was applied to younger adult-derived myotubes; no reduction in myotube thickness was observed. MAFbx expression was significantly increased in response to non-lean EVs (p < 0.05). RNA-seq revealed 471 differentially expressed genes (DEGs) in EV-treated versus untreated cells and 293 DEGs between lean and non-lean EV conditions, with enrichment in inflammatory (TNF and IL1B), oxidative stress, mitochondrial and chromatin pathways. Small RNA-seq identified seven differentially expressed miRNAs (annotated using miRBase release 22.1), including miR-150-5p and miR-193b-5p, both significantly upregulated in non-lean EVs and validated by qPCR. Inhibiting miR-150-5p partially rescued myotube thickness (10.5 ± 1.37 μm vs. 8.7 ± 1.66 μm, p < 0.05) and reduced MAFbx expression.
CONCLUSIONS: EVs from non-lean adipose tissue drive muscle atrophy and transcriptional changes in an age-dependent manner. These effects are partially mediated by miR-150-5p, highlighting a mechanistic role for EV cargo in adipose-muscle signalling. Targeting EV-derived miRNAs may offer a novel strategy to combat muscle loss in obesity and ageing.

Keywords:  adipose; atrophy; extracellular vesicles; miRNA; obesity; sarcopenia

DOI:  https://doi.org/10.1002/jcsm.70204