bims-musmir 2026-01-25 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–01–25
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Association Between Abnormal DNA Methylation and Altered Transcriptome in Muscle Five Years After Critical Illness.
Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.
Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.
Puerarin-loaded injectable hydrogel mitigates skeletal muscle wasting in colorectal cancer cachexia by targeting inflammatory signaling and improving protein homeostasis.
Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.
Distinct Myogenic Stages Recapitulate Transcriptomic Networks in COPD Cachexia.
METTL16-m6A-PGC-1α axis contributes to exercise-induced mitochondrial adaptations in skeletal muscle of high-fat diet-fed insulin-resistant mice.
Transcriptomic and functional profiling reveal autophagy inhibition and persistent bioenergetic collapse following parallel photodamage to lysosomes and mitochondria.
Biochemical principles of miRNA targeting in flies.
Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.
Caloric restriction modifies small RNA profiles and engages age-related molecular pathways in the CALERIE trial.
Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.
Changes in Components of Sarcopenia Diagnostic Criteria Throughout the Surgical Treatment of Oesophagogastric Cancer Surgery: A Prospective Longitudinal Study.

J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70170

Association Between Abnormal DNA Methylation and Altered Transcriptome in Muscle Five Years After Critical Illness.

Ceren Uzun Ayar, Fabian Güiza, Inge Derese, Greet Van den Berghe, Ilse Vanhorebeek.

   BACKGROUND: Critically ill patients requiring intensive care unit (ICU) admission suffer from muscle weakness that persists for years. Recently, altered RNA expression was documented in muscle of former ICU patients 5 years after critical illness that suggested disrupted mitochondrial function, disturbed lipid metabolism and fibrosis, of which many associated with the former patients' long-term loss of muscle strength. We hypothesized that abnormal DNA methylation detectable years after critical illness associates with these abnormal RNA expression patterns, as a potential biological basis for the persistent loss of muscle strength.
METHODS: Genome-wide DNA methylation was assessed (Infiniumv2-HumanMethylationEPIC-BeadChips) in skeletal muscle biopsies from 118 former ICU patients harvested 5 years after critical illness (79.6% male, median 58 years, median BMI 27.3 kg/m2) and 30 controls who never required ICU admission (76.7% male, median 61 years, median BMI 26.4 kg/m2). Differentially methylated positions (DMPs) in former patients versus controls were identified, adjusting for age, sex, and BMI (minfi-package in R, Benjamini-Hochberg false-discovery-rate < 0.05), followed by pathway over-representation of affected genes. Spearman correlations between DMP methylation and RNA expression were compared among groups of RNA with Z-test and Kolmogorov-Smirnov test. Risk factors for abnormal DNA methylation were identified with multivariable linear regression.
RESULTS: As compared with controls, former ICU patients showed 7379 DMPs (average difference 2.6% ranging up to 24.9%). They were associated with 1334 unique genes, enriched for muscle contraction, vascular development, cell differentiation and signal transduction. DMPs correlated more strongly with differentially expressed RNAs (DERNAs) than with non-differentially expressed RNAs (18.1% vs. 1.7% correlations with |rho| > 0.3, p < 2.2 × 10-16). Such correlations were more abundant among DERNAs associated with reduced muscle strength vs. those not associated (24.4% vs. 12.5%), also within the previously identified disrupted pathways (mitochondrial function 23.3% vs. 10.9%, lipid metabolism 15.9% vs. 7.2%, fibrosis 44.3% vs. 5.8%, all p < 2.2 × 10-16). Older age, female sex, in-ICU treatment with glucocorticoids, benzodiazepines, early parenteral nutrition and opioids and insulin and antipsychotic medication at follow-up were most notably associated with more abnormal DNA methylation.
CONCLUSIONS: Abnormal DNA methylation in muscle biopsied 5 years after critical illness associated with long-term altered RNA expression that has been linked to lower muscle strength. These data suggest a possible epigenetic basis for this long-term sequel after critical illness. Abnormal DNA methylation was also found to associate with (possibly) avoidable risk factors during and after ICU stay. These findings may open perspectives for prevention and possibly treatment of long-term muscle weakness after critical illness.

Keywords:  DNA methylation; critical illness; epigenetics; muscle weakness; post‐intensive care syndrome; transcriptome

DOI:  https://doi.org/10.1002/jcsm.70170
J Nutr. 2026 Jan 20. pii: S0022-3166(26)00016-7. [Epub ahead of print] 101367

Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.

Luisa F Castillo, Katarina E Heyden, Abigail R Williamson, Wenxia Ma, Olga V Malysheva, Nathaniel M Vacanti, Anna E Thalacker-Mercer, Martha S Field.

   BACKGROUND: Vitamin B12 is a cofactor in folate-mediated one-carbon metabolism (FOCM), which generates nucleotides (thymidylate (dTMP) and purines) and methionine. Depressed de novo thymidylate (dTMP) synthesis leads to uracil accumulation in DNA.
OBJECTIVE: The purpose of this study was to determine how B12 availability affects mitochondrial DNA (mtDNA) integrity and mitochondrial function in skeletal muscle. B12 deficiency was modeled in young-adult mice. Intramuscular B12 injection in aged mice assessed the role of B12 supplementation in age-related changes in skeletal muscle.
METHODS: Male methionine synthase knockdown (Mtr+/-) and wild-type littermates (Mtr+/+) were weaned to either an AIN93G-based control (C) diet containing 25 μg/kg vitamin B12 (Mtr+/+, n=8; Mtr+/-, n=9) or a B12-deficient (-B12) diet containing 0 μg/kg vitamin B12 (n=9 per genotype) for seven weeks. Aged (20-22mo) male C57BL/6N mice were acclimated to an AIN93G control diet four weeks, then received either weekly injections of saline (vehicle control [30 uL 0.9% NaCl], n=5) or B12 (0.65 μg per 30uL 0.9% NaCl; n=6) in each of two hindleg muscles [1.25 μg B12 total]) for eight weeks. Outcomes measured included maximal oxygen consumption rate (OCR), uracil in mtDNA (a biomarker of mtDNA integrity), mtDNA copy number, and mitochondrial mass. Data were analyzed using a two-way ANOVA in the Mtr+/- mouse model exposed to B12-deficient diets and by a student's t-test for B12 supplementation in aged mice.
RESULTS: The tibialis anterior (TA) muscle from Mtr+/- mice exhibited 50% lower (p=0.01) maximal respiratory capacity of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B12 diet lowered maximal capacity of complex I in mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) by 25% (p=0.02). Uracil in mitochondrial DNA (mtDNA) in red muscle and gastrocnemius was elevated ∼10 fold with exposure to -B12 diet (p=0.04 and p<0.001, respectively). In aged mice, gastrocnemius complex IV activity was increased 2-fold with intramuscular B12 supplementation (p=0.04).
CONCLUSIONS: Exposure to a B12-deficient diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in skeletal muscle. B12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice, a model of age-related skeletal muscle decline.

Keywords:  Vitamin B12; mitochondrial DNA; oxidative phosphorylation; skeletal muscle; thymidylate; uracil

DOI:  https://doi.org/10.1016/j.tjnut.2026.101367
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70183

Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.

Lindsey J Anderson, Lu Xia, Haiming Kerr, Marin Cabrera, Fabien Chu, Jaqueline Rose, Peter C Wu, Atreya Dash, Sina A Gharib, Jose M Garcia.

   BACKGROUND: Treatments for cancer cachexia, defined as involuntary weight and muscle mass loss leading to significant functional impairment, remain unavailable partly due to insufficient improvement of clinically meaningful outcomes in current trials. By reflecting downstream effects of cellular function, metabolomics may identify mechanisms contributing to poor functional performance. Previous metabolomic studies in cancer cachexia have identified alterations in amino acid metabolism with weight loss or low muscularity; none have examined perturbations with poor physical function. We hypothesized that distinct metabolic signals in plasma and muscle are associated with weight loss, low muscle mass, and impaired function in cancer cachexia.
METHODS: We enrolled patients planning elective laparotomy for gastrointestinal or genitourinary cancer. Handgrip strength (HGS), stair climb power (SCP), and fasting plasma were collected within 2 weeks prior to surgery; rectus abdominis samples were obtained during surgery. Metabolomic perturbations associated with physical function (HGS, SCP), muscularity (lumbar cross-sectional area 'CSA' from opportunistic CT), or weight loss (> 5% over previous 6 months) were examined in plasma and muscle. The Mann-Whitney U-test compared metabolite abundance between weight-losing and weight-stable patients, while Spearman's correlation tested associations of abundance with CSA, HGS, or SCP. The 'Globaltest' method assessed pathway alterations with weight loss, CSA, HGS, or SCP; the Benjamini-Hochberg adjustment was used to control for false discovery.
RESULTS: Patients (N = 72) were male, median age 65 [interquartile range: 59-70], with 57% genitourinary cancer. Plasma and skeletal muscle metabolomic data were collected (N = 64 and N = 68, respectively). Weight loss was associated with significantly altered microbial, amino acid/derivative, fatty acid/lipid, and caffeine-related metabolism pathways in plasma (adjusted p < 0.1). Lower CSA was associated with significantly altered fatty acid/lipid, galactose, glycerophospholipid, and histidine metabolism and bile secretion pathways in skeletal muscle (adjusted p < 0.1). Worse HGS was nominally associated with altered plasma branched chain amino acid biosynthesis and altered skeletal muscle glutathione metabolism (unadjusted p ≤ 0.05), while worse SCP was nominally associated with altered skeletal muscle amino sugar/nucleotide sugar metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis (unadjusted p ≤ 0.05).
CONCLUSIONS: Significant metabolomic alterations in plasma and skeletal muscle characterized cancer-related weight loss and reduced CSA, respectively. Nominal, function-specific alterations were detected with worse HGS and SCP, which were distinct from those associated with weight loss or low CSA. Future larger studies may further characterize metabolomic profiles related to various functional outcomes and guide development of therapeutic targets to improve functional performance.

Keywords:  cancer cachexia; functional impairment; handgrip; metabolomics; skeletal muscle; stair climb

DOI:  https://doi.org/10.1002/jcsm.70183
bioRxiv. 2025 Dec 07. pii: 2025.12.03.692123. [Epub ahead of print]

Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.

Jer-En Hsu, Qingyang Zhao, Weiqiu Cheng, Hyun-Min Kang, Susan V Brooks, Myungjin Kim, Jun Hee Lee.

Skeletal muscle is a structurally organized and functionally diverse organ composed of heterogeneous myofiber types and supporting non-myocyte populations that act in concert to generate force, regulate metabolism, and maintain systemic homeostasis. Myopathies occur in many different diseases, but the mechanisms that drive these muscle pathologies are still largely unknown, partly because conventional approaches cannot link histopathological features to molecular states at single-fiber resolution. To address this challenge, we brought histopathology and spatial transcriptomics together by applying high-resolution Seq-Scope technology to a rodent model of mTORC1 hyperactivation, which produces diverse pathological alterations within individual myofibers. Cross-sections from extensor digitorum longus (EDL) and soleus (SOL), two muscles with distinct fiber-type compositions, were profiled to determine how transcriptome changes are linked to histopathological outcomes. Our analyses reveal that mTORC1 hyperactivation elicits distinct, fiber-type-dependent pathological programs. Type I and IIa fibers, abundant in SOL but scarce in EDL, were largely resistant to mTORC1-induced pathology, exhibiting only minimal morphological alterations and no fiber type-specific responses beyond those commonly observed throughout the tissue. In contrast, type IIx fibers, shared between both muscles, diverged into opposing fates: in SOL, they underwent abnormal enlargement driven by sustained growth signaling, cytoskeletal remodeling, and impaired proteostasis with defective autophagy; whereas in EDL, they developed basophilia characterized by lipid-supported respiration fueling excessive ribonucleotide synthesis and RNA accumulation. Within the same muscle, type IIb fibers displayed striking heterogeneity with discrete transcriptional states encompassing canonical stress responses, oxidative metabolic activation, and developmental reprogramming. In parallel, non-myocytic populations, including activated macrophages and fibroblasts, accumulated preferentially in SOL, forming a fibrotic microenvironment supporting inflammation, tissue remodeling and hypertrophy. Taken together, these findings reveal that sustained mTORC1 signaling disrupts muscle homeostasis through distinct metabolic and structural routes, directly linking histopathological phenotypes to their molecular states at single-fiber resolution.

DOI: https://doi.org/10.64898/2025.12.03.692123
Mater Today Bio. 2026 Feb;36 102751

Puerarin-loaded injectable hydrogel mitigates skeletal muscle wasting in colorectal cancer cachexia by targeting inflammatory signaling and improving protein homeostasis.

Ruibing Li, Qiang Tao, Haonan Huang, Xinhui Zhu, Huanmiao Zhan, Xinyou Wang, Yijia Lin, Chong Wang.

  Cancer cachexia (CC) is a complex, tumor-induced metabolic syndrome characterized by progressive skeletal muscle atrophy, systemic inflammation, and refractoriness to nutritional intervention, contributing to functional decline and increased mortality. Effective targeting of CC-induced skeletal muscle atrophy are major challenges in clinical treatment. Systemic administration of puerarin (PUE) is limited by poor oral bioavailability, rapid clearance, and lack of tissue-targeting capability, resulting in suboptimal therapeutic concentrations at the affected muscle tissue. This study aimed to construct a multifunctional drug delivery system: PUE was added to the oxidized dextran (OD) solution and then mixed with the phenylboronic acid (PBA)-modified carboxymethyl chitosan (CMCS-PBA) solution to form the CPO/PUE hydrogel. This injectable hydrogel overcomes the limitations of systemic PUE delivery by enabling sustained local release directly at the target muscle tissue, thereby enhancing therapeutic efficacy while minimizing systemic exposure. Both in vitro and in vivo experiments confirmed that the constructed CPO/PUE exhibited excellent targeting ability, significant anti-inflammatory effects, strong antioxidant activity, and pro-angiogenic effects. Experimental analysis showed that the CPO/PUE hydrogel could achieve sustained release of PUE, regulate the expression of muscle apoptosis-related proteins, inhibit the activation of the JAK2-STAT3 and NF-κB inflammatory pathways, and alleviate the suppression of the AKT-mTOR pathway. This delivery system effectively mitigates local muscle atrophy at the injection site in cancer cachexia, demonstrating a highly promising and significant therapeutic strategy.

Keywords:  Cancer cachexia; Injectable hydrogel; Muscle atrophy; Puerarin

DOI:  https://doi.org/10.1016/j.mtbio.2025.102751
Front Mol Neurosci. 2025 ;18 1686230

Potential role of stress granules and myogranules in amyotrophic lateral sclerosis.

Saddam Muhammad Ishaq, Aaron P Russell.

  Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.

Keywords:  TDP-43; amyotrophic lateral sclerosis; brain; myogranule; skeletal muscle; spinal cord; stress granules

DOI:  https://doi.org/10.3389/fnmol.2025.1686230
bioRxiv. 2025 Dec 05. pii: 2025.12.03.692216. [Epub ahead of print]

Distinct Myogenic Stages Recapitulate Transcriptomic Networks in COPD Cachexia.

Hanna Sothers, Bitota Lukusa-Sawalena, Kaleen M Lavin, Wenxia Ma, Joe W Chiles, Richard Casaburi, Rakesh Patel, J Michael Wells, Mohamed Kazamel, Harry B Rossiter, Anna Thalacker-Mercer, Merry-Lynn N McDonald.

Background: Cachexia is an extrapulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) characterized by weight loss and muscle wasting. Transcriptomic profiling of vastus lateralis biopsies enables profiling of COPD-cachexia relevant dysregulation. As obtaining muscle biopsies is invasive and yields limited tissue, human muscle derived cultures (HMDC) may enable mechanistic research into cachexia. However, questions remain regarding the extent to which HMDC recapitulate transcriptomic signatures of bulk skeletal muscle in COPD-cachexia. To address this gap, we tested whether COPD and COPD-cachexia associated transcriptional dysregulation signatures in bulk skeletal muscle are preserved in derived myoblasts, myocytes, and myotubes.
Methods: Vastus lateralis biopsies were collected from 13 (6M/7F, 64±9 years) participants; COPD n=5, COPD-cachexia n=4, and 4 age-matched controls. Cachexia was defined using a composite measure of weight loss coupled with reduced muscle strength, fatigue, anorexia, low muscle mass and/or systemic inflammation. Satellite cells were isolated and differentiated into myoblasts, myocytes, and myotubes. Differential gene expression testing, generated from RNA-sequencing, identified transcripts significantly dysregulated (p>0.05) in bulk tissue. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules of co-expressed genes at the whole-transcriptome and mitochondrial transcriptome levels. Bulk tissue modules were tested for preservation in HMDC (Z-summary >2) and correlated with clinical traits. Gene set enrichment analysis was performed for all modules.
Results: 1,379 genes were significantly differentially expressed in bulk samples from all COPD participants compared to controls. The top upregulated gene was IL32 (L2FC=4.5, p=1.3×10 - 3 ) and top downregulated CGN (L2FC=-5.8, p=8.8×10 - 3 ). A total of 632 genes were significantly differentially expressed in bulk samples from COPD participants with and without cachexia. The top upregulated gene was SEMA4F (L2FC=5.0, p=6.9×10 - 4 ) and top downregulated ARC (L2FC=-4.9, p=3.1×10 - 2 ). WGCNA generated 9 modules (Modules 1 - 9) at the whole-transcriptome level and 2 modules (Modules A and B) at the mitochondrial transcriptome level. Modules 1, 4, 5, and 9 were significantly correlated with COPD-cachexia. Of these, module 1 was preserved in myoblasts and modules 4, 5 and 9 in myocytes. These modules are enriched with genes involved in metabolic and inflammatory remodeling, catabolic stress and atrophy, and chromatin-driven regeneration.
Conclusions: These results provide a foundation for using myocytes and myoblasts as in vitro models of degeneration and repair pathway dysregulation in COPD-cachexia. Several modules were preserved between bulk skeletal muscle and HMDC, suggesting HMDC have utility for studying COPD-cachexia.

DOI: https://doi.org/10.64898/2025.12.03.692216
BMC Biol. 2026 Jan 22.

METTL16-m6A-PGC-1α axis contributes to exercise-induced mitochondrial adaptations in skeletal muscle of high-fat diet-fed insulin-resistant mice.

Cong Chen, Cai Jiang, Qing Xiang, Yue Hu, Huijuan Wu, Chunxiu Huang, Huanghao Zhou, Ying Xu, Meijin Hou, Weilin Liu, Xiao Han.

   BACKGROUND: The dynamic change of N6-methyladenosine (m6A) modification on substrate RNA molecules plays a critical role in different biological processes and disease pathogenesis. Although the beneficial effects of exercise training (ET) on skeletal muscle insulin resistance (IR) are well-established, the contribution of RNA m6A modification in ET-related adaptations in high-fat diet (HFD)-induced IR remains unclear.
RESULTS: In this study, we show that exercise stimulation triggers a dynamic shift in skeletal muscle m6A modification levels during HFD consumption. As a key m6A methyltransferase, METTL16 was downregulated in HFD-fed mice and upregulated by ET at both the mRNA and protein levels. In vitro, METTL16 knockdown disrupted mitochondrial ultrastructure, reduced electron transport chain complex activities, and decreased the NAD+/NADH ratio, ATP content, and mitochondrial membrane potential, indicating impaired mitochondrial function. Concomitantly, METTL16 loss lowered m6A on PGC-1α mRNA, reducing its stability and protein abundance and blunting insulin signalling, whereas PGC-1α overexpression partially reversed these defects.
CONCLUSIONS: In conclusion, METTL16 functions as an exercise-responsive m6A methyltransferase that may modulate PGC-1α, mitochondrial function, and insulin-related signalling in HFD skeletal muscle, implicating the METTL16-m6A-PGC-1α axis in exercise-induced metabolic adaptations.

Keywords:  Exercise; Insulin resistance; METTL16; Mitochondrial function; PGC-1α

DOI:  https://doi.org/10.1186/s12915-026-02519-5
J Photochem Photobiol B. 2026 Jan 07. pii: S1011-1344(26)00011-4. [Epub ahead of print]275 113364

Transcriptomic and functional profiling reveal autophagy inhibition and persistent bioenergetic collapse following parallel photodamage to lysosomes and mitochondria.

Márcia Silvana Freire Franco, Felipe Gustavo Ravagnani, Suely Kazue Nagahashi Marie, Sueli Mieko Oba-Shinjo, Leonardo Vinicius Monteiro de Assis, Maurício S Baptista.

  Photodynamic therapy (PDT) using 1,9-dimethyl methylene blue (DMMB) induces coordinated mitochondrial and lysosomal damage and results in strong cellular death induction. However, the underlying transcriptional regulation in response to DMMB remains elusive. We compared the transcriptome response of photoactivated DMMB (paDMMB) to the gene signature triggered by autophagy-modulating agents: rapamycin (an autophagy activator) and bafilomycin A1 (an autophagy inhibitor). Transcriptome analysis revealed a pronounced transcriptomic response to paDMMB, with 884 differentially expressed genes (DEGs), compared to 291 for bafilomycin and 154 for rapamycin. paDMMB treatment upregulated genes associated with autophagy, mitochondrial stress responses, and proteostasis, while downregulating genes involved in miRNA processing and lipid catabolism. Rapamycin treatment downregulated amino acid biosynthesis pathways, while upregulating processes associated with nutrient starvation. Conversely, bafilomycin treatment upregulated genes related to lipid metabolism, while suppressing cytoskeletal programs. We observed that approximately 80% of bafilomycin DEGs also changed in paDMMB-treated cells, and about 96% of these shared genes showed concordant regulation. This suggests that the paDMMB molecular signature is consistent with the inhibition of autophagic flux. Among the several biological processes affected by paDMMB, mitochondrial-related processes were enriched. To determine whether the acute transcriptome changes caused by paDMMB led to persistent functional effects, we stimulated cells with DMMB and assessed mitochondrial respiration after a recovery period. paDMMB reduced basal respiration, ATP production, proton leak, and maximal respiration. These effects were not further altered by bafilomycin co-treatment but were markedly exacerbated by rapamycin. Collectively, we show that paDMMB leads to a transcriptome rewiring, closely resembling autophagy inhibition with a sustained mitochondrial dysfunction. These findings provide a valuable resource to understand the interplay between DMMB-induced lysosomal stress, transcriptional regulation, and PDT.

Keywords:  1,9-dimethyl methylene blue; Autophagy; Cellular stress response; Mitochondrial dysfunction; Photodynamic therapy; Transcriptomics

DOI:  https://doi.org/10.1016/j.jphotobiol.2026.113364
Nat Commun. 2026 Jan 20.

Biochemical principles of miRNA targeting in flies.

Joel Vega-Badillo, Phillip D Zamore, Karina Jouravleva.

MicroRNAs direct Argonaute proteins to repress complementary target mRNAs via mRNA degradation or translational inhibition. While mammalian miRNA targeting has been well studied, the principles by which Drosophila miRNAs bind their target RNAs remain to be fully characterized. Here, we use RNA Bind-n-Seq to systematically identify binding sites and measure their affinities for five highly expressed Drosophila miRNAs. Our results reveal a narrower range of binding site diversity in flies compared to mammals, with fly miRNAs favoring canonical seed-matched sites and exhibiting limited tolerance for imperfections within these sites. We also identified non-canonical site types, including nucleation-bulged and 3'-only sites, whose binding affinities are comparable to canonical sites. These findings establish a foundation for future computational models of Drosophila miRNA targeting, enabling predictions of regulatory outcomes in response to cellular signals, and advancing our understanding of miRNA-mediated regulation in flies.

DOI: https://doi.org/10.1038/s41467-026-68360-0
Cell Commun Signal. 2026 Jan 20.

Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.

Huy Quang Dang, Therése Forssén, Spyridon Pantelios, Aisegkioul Nteli Chatzioglou, Ewa Kurzejamska, C Theresa Vincent, Yasir Ibrahim, Anders P Mutvei.

  The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling-thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.

Keywords:  Amino acid deprivation; Catabolically impaired lysosomes; Lysosome positioning; MTORC1; PI3K-Akt signaling; Rab7; Rap1

DOI:  https://doi.org/10.1186/s12964-026-02659-9
iScience. 2026 Jan 16. 29(1): 114514

Caloric restriction modifies small RNA profiles and engages age-related molecular pathways in the CALERIE trial.

CALERIE™ Investigators

  Caloric restriction (CR) extends lifespan and enhances healthspan across species. In humans, the CALERIE Phase 2 trial demonstrated that CR improves inflammation, cardiometabolic health, and molecular aging. To explore underlying mechanisms, we examined CR-induced changes vs. ad libitum (AL) in small non-coding RNAs (smRNAs) across plasma, muscle, and adipose tissue. Using smRNA sequencing, we analyzed microRNAs (miRs) and piwi-interacting RNAs (piRs) over 12 and 24 months, comparing CR levels (%CR) and group assignments (CR vs. AL). We identified 16 smRNAs associated with %CR and 41 with CR vs. AL. Although tissue-specific expression varied, shared pathways emerged, including insulin signaling, circadian rhythm, cell cycle regulation, and stress response. Cross-species analysis revealed 17 miRs altered by CR in both humans and rhesus monkeys. These findings suggest smRNAs are key molecular mediators of CR's effects on aging and longevity, offering insight into biological mechanisms of CR and potential targets for age-related interventions.

Keywords:  clinical genetics; human metabolism

DOI:  https://doi.org/10.1016/j.isci.2025.114514
Sci Rep. 2026 Jan 17.

Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.

Olivier Reynaud, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marc P Lussier, Sabah Na Hussain, Gilles Gouspillou.

Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD.

DOI: https://doi.org/10.1038/s41598-025-34223-9
J Inherit Metab Dis. 2026 Jan;49(1): e70147

Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.

Paloma Martín-Jimenez, Laura Bermejo-Guerrero, Luz Edith Ochoa, María Navarro-Riquelme, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, Adrián González Quintana, Ana Bermejo-Moriñigo, Violeta González-Méndez, Cristina Martín-Arriscado Arroba, Dimitrii Smirnov, Nikita Konstantinovskiy, Joaquín Arenas, Miguel Ángel Martin, Alberto Blázquez, Cristina Domínguez-González.

  Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy with variable presentations, including late-onset forms beginning after age 12. Unlike early-onset disease, the natural history of late-onset TK2d remains poorly defined. We conducted a prospective, single-centre natural history study of 11 untreated patients with late-onset TK2d over 24 months. The median age at symptom onset was 27.2 years. Clinical phenotypes included progressive myopathy (n = 7), chronic progressive external ophthalmoplegia plus (n = 2), and exercise intolerance (n = 2). Most patients (72%) required non-invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic TK2 variants, with p.Lys202del being the most common (13/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the sartorius, gracilis and gluteus maximus, whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six-minute walk distance of 479.5 m, and a 100-m run time of 60.5 s. Serum GDF15 levels were elevated (median 2747.5 pg/mL) and significantly correlated with motor and respiratory function. Over 2 years, patients showed measurable clinical deterioration, with declines in NSAA (-2.65 points), FVC (-9.11%), and worsening 100-meter run times (+6 s). This study provides the first prospective longitudinal characterization of late-onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.

Keywords:  GDF15; TK2 deficiency; biomarkers; late‐onset; mitochondrial myopathy; natural history

DOI:  https://doi.org/10.1002/jimd.70147
J Hum Nutr Diet. 2026 Feb;39(1): e70205

Changes in Components of Sarcopenia Diagnostic Criteria Throughout the Surgical Treatment of Oesophagogastric Cancer Surgery: A Prospective Longitudinal Study.

Lisa C Murnane, Adrienne K Forsyth, Jim Koukounaras, Kalai Shaw, Eldho Paul, Wendy A Brown, Audrey C Tierney, Paul R Burton.

   INTRODUCTION: Low skeletal muscle is prevalent and associated with poorer outcomes after oesophagogastric (OG) cancer surgery. However, sarcopenia, including strength and function, is less commonly assessed. Therefore, we aimed to describe the prevalence of sarcopenia and changes in diagnostic criteria within 1 year of OG cancer surgery.
METHODS: This prospective observational study included OG cancer surgery patients from 2018 to 2021. Body composition was assessed using computed tomography (CT) and bioimpedance spectroscopy (BIS). Low CT-defined skeletal muscle index (SMI) and myosteatosis were defined using published thresholds. Low fat-free mass index (FFMI) cut points were < 17 kg/m2 for men and < 15 kg/m2 for women. Hand grip strength (HGS, kg) and 6-metre walk test (metres/second) measured strength and function, respectively. Sarcopenia, defined using the European Working Group on Sarcopenia in Older People 2019 criteria, was assessed preoperatively, 2-, 6- and 12-weeks post-discharge and 6 and 12 months postoperatively.
RESULTS: Forty-eight patients, predominantly male (63%) with a mean (SD) age of 64 (10.1) years, were included preoperatively, and 25 patients at 1 year. Low SMI (50%) and myosteatosis (50%) were prevalent preoperatively. Fewer patients had low FFMI (6%), low HGS (17%), and low walk speed (6%). The prevalence of Sarcopenia-CT was 15% preoperatively and 12% at 1-year (p = 0.32), and sarcopenia-BIS was 2% preoperatively and 3% at 1-year (p = 0.60).
CONCLUSIONS: Despite a high prevalence of low SMI and myosteatosis, sarcopenia was less common. Low muscle mass, with adequate strength and function, is a prominent feature. Given the negative outcomes of low SMI, muscle assessment remains a valuable and clinically meaningful measure.

Keywords:  cancer; function; muscle mass; sarcopenia; strength; surgery

DOI:  https://doi.org/10.1111/jhn.70205