bims-musmir 2026-04-05 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–04–05
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
Overexpression of miR-455-3p enhances mitophagy, synaptic and mitochondrial proteins in Alzheimer's disease.
ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
Exercise-related microRNAs in Caenorhabditis elegans regulate calcium homeostasis and mitochondrial dynamics: Conserved pathways, divergent microRNAs.
Anabolic resistance in cancer cachexia: a role for sex and chemotherapy.
Transcriptional Remodeling of Human Skeletal Muscle Following Sleep Restriction in Postmenopausal Women.
Dual pathways of TFEB activation under lysosomal stress: ATG conjugation-dependent and -independent modes.
ADARs mediate distinct RNA editing activity and gene regulation in the Caenorhabditis elegans germline.

Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2508286123

Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.

Esther García-Domínguez, Cristina García-Domínguez, José Luis Cabrera-Alarcón, María Del Mar Muñoz-Hernández, Pablo Hernansanz-Agustín, Andrea Curtabbi, Julio Domenech-Fernandez, Enrique Calvo, Jesús Vázquez, Antonio L Serrano, Pura Muñoz-Cánoves, Gloria Olaso-González, José Antonio Enríquez, María Carmen Gómez-Cabrera.

  Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.

Keywords:  frailty; health span; mitochondrial function; proteomics; sarcopenia

DOI:  https://doi.org/10.1073/pnas.2508286123
Mitochondrion. 2026 Apr 01. pii: S1567-7249(26)00041-3. [Epub ahead of print] 102151

Overexpression of miR-455-3p enhances mitophagy, synaptic and mitochondrial proteins in Alzheimer's disease.

Jangampalli Adi Pradeepkiran, Madhuri Bandaru, Md Ariful Islam, Sudhir Kshirsagar, Rainier Vladlen Alvir, Upasana Mukherjee, P Hemachandra Reddy.

  MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression, neural development and plasticity in Alzheimer's disease (AD). Our lab recently discovered molecular links between miR-455-3p and AD. miR-455-3p is known to regulate APP expression, thereby influencing amyloid beta (Aβ) generation. Using pronuclear injection and CRISPR/Cas9 technologies, we created miR-455-3p transgenic (TG) and knockout (KO) mice. Remarkably, the miR-455-3p TG mice displayed an extended lifespan (by approximately 5 months) compared to wild-type (WT) mice, whereas miR-455-3p KO mice had a reduced lifespan (by 4 months). Behaviorally, miR-455-3p TG mice outperformed cognitive tasks such as the Morris water maze and Y-maze, indicating improved spatial memory and learning. To explore miR-455-3p's role in AD progression, we crossed miR-455-3p TG and miR-455-3p KO mice with the humanized amyloid beta knock-in (hAbKI) mouse model, which mimics late-onset AD features. The resulting experimental groups included WT, miR-455-3p TG, miR-455-3p KO, hAbKI, miR-455-3p TG X hAbKI, and miR-455-3p KO X hAbKI. In the current study, we investigated mitochondrial dynamics, mitochondrial biogenesis, mitophagy and synaptic proteins in all six groups of 12-month-old male and female mice. We focused on examining the expression of, mitophagy regulators (PINK1, Parkin), and synaptic markers (PSD95, Synaptophysin), mitochondrial biogenesis regulators (PGC1α, NRF1, TFAM) and dynamic proteins (DRP1, FIS1, Mfn1/2, OPA1) in the cortex of 12-month-old animals using western blot and immunofluorescence analyses. We also studied spine density in hippocampal sections for the mice groups in a Golgi-cox staining assay. We found miR-455-3p overexpression enhances mitophagy, mitochondrial biogenesis, dynamics proteins and spine density, in hAbKI mice. Depleted miR-455-3p exacerbates mitochondrial defects, defective mitophagy and synaptic loss in hAbKI mice. Our findings highlight miR-455-3p as a promising therapeutic target that modulates multiple pathological pathways in AD. This is the first genetic crossing study of miR-455-3p TG/KO mice with late onset AD, hAbKI mice.

Keywords:  Alzheimer’s disease; Humanized Abeta knockin mice; Mir-455-3p transgenic mice; Mitochondria; Mitochondrial biogenesis; Mitophagy

DOI:  https://doi.org/10.1016/j.mito.2026.102151
Aging (Albany NY). 2026 Mar 27. 18(1): 213-233

ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.

Victoria C Sanfrancesco, David A Hood.

  In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response

DOI:  https://doi.org/10.18632/aging.206365
FEBS J. 2026 Mar 30.

Exercise-related microRNAs in Caenorhabditis elegans regulate calcium homeostasis and mitochondrial dynamics: Conserved pathways, divergent microRNAs.

Qin Xia, Jiwang Tang, José C Casas-Martinez, Penglin Li, Maria Borja-Gonzalez, Leo R Quinlan, Katarzyna Goljanek-Whysall, Brian McDonagh.

  Exercise can help mitigate age-related muscle atrophy, promoting mitochondrial function, Ca2+ homeostasis and regulating gene expression. MicroRNAs (miRs) are crucial post-transcriptional regulators of gene expression, fine-tuning protein levels to maintain cellular homeostasis. In Caenorhabditis elegans, a 5-day swimming regimen increased mitochondrial content, lifespan and fitness. Small RNA sequencing identified exercise specific miRs, including increased levels of cel-miR-57-5p and cel-miR-249-3p, and decreased levels of cel-miR-72-3p and cel-miR-77-5p. mir-57 and mir-249 mutant strains had enhanced fertility, survival and lifespan, whereas mir-72 and mir-77 mutant strains had diminished fertility, survival and lifespan. The exercise-related miRs identified in C. elegans did not have conserved mammalian orthologs. Exercise regulated mammalian miRs were identified from the literature including mmu-miR-181a-5p, mmu-miR-199a-5p and mmu-miR-378a-3p. Treatment of murine myoblasts with mmu-miR-181a-5p and mmu-miR-378a-3p enhanced mitochondrial content, autophagy markers and myogenesis, while mmu-miR-199a-5p impaired these processes. Exercise-related miRs identified in C. elegans target genes regulating Ca2+ homeostasis such as ipp-5 (inositol Polyphosphate-5-phosphatase), sca-1 (Ca2+ transporting ATPase) and ncx-2 (mitochondrial Na+/Ca2+ antiporter). It was also confirmed that mmu-miR181a-5p targets Inpp5a and treatment with antogmiR-181a decreased Ca2+ handling in myotubes. Similarly, mmu-miR-378a-3p and cel-miR-249-3p target Kinase Suppressor of Ras (Ksr1)/ksr-2, involved in the MAPK pathway. Despite direct conservation of exercise-related miRs from nematodes to mammals, there are putative common regulatory pathways contributing to exercise-induced adaptations.

Keywords:  Caenorhabditis elegans; DEAD‐box helicase 3 X‐linked (Ddx3x); Kinase Suppressor of Ras (Ksr1)/ksr‐2; exercise; inositol polyphosphate‐5‐phosphatase (Inpp5a); microRNA arm switching; peroxiredoxin 2

DOI:  https://doi.org/10.1111/febs.70502
Curr Opin Clin Nutr Metab Care. 2026 May 01. 29(3): 277-286

Anabolic resistance in cancer cachexia: a role for sex and chemotherapy.

Tanner Jenkins, Quan Zhang, James A Carson.

   PURPOSE OF REVIEW: The purpose of this review is to highlight recently published research that can provide insight into how either sex or chemotherapeutics can impact cancer regulation of muscle anabolic resistance. Critical knowledge gaps are emphasized that are linked to cancer and treatment disruptions to muscle anabolic signaling. We speculate and propose a rationale for estrogen's protective effect against cancer-induced muscle anabolic resistance in females. Furthermore, there is growing evidence that many cancer treatments have the potential to exacerbate muscle anabolic resistance in both males and females. We present current evidence and speculate on how nutritional interventions could serve as key modulators of cancer-induced anabolic resistance in these conditions.
RECENT FINDINGS: Recently published studies have reinforced that sex impacts the regulation of cancer cachexia in several established preclinical models, with males often developing more severe cachexia when compared to females. Importantly, recent research has established these sex differences at the transcriptomic level. Recent research has also strengthened the link between hypogonadism as a driver of cancer cachexia in preclinical models. Furthermore, chemotherapy has the potential to exacerbate muscle anabolic resistance.
SUMMARY: There is a growing body of literature that provides a strong rationale for further investigation into the impact of sex and chemotherapy on the cancer regulation of muscle anabolic resistance.

Keywords:  chemotherapy; sex; skeletal muscle

DOI:  https://doi.org/10.1097/MCO.0000000000001219
Physiol Genomics. 2026 Mar 28.

Transcriptional Remodeling of Human Skeletal Muscle Following Sleep Restriction in Postmenopausal Women.

Hari Naga Sai Kiran Suryadevara, R Caitlin Hebert, Jaroslaw Staszkiewicz, Eric Ravussin, Kara L Marlatt, Prachi Singh, Sujoy Ghosh.

  Sleep is a critical regulator of metabolic health, but its impact on skeletal muscle remains underexplored. Given the muscle's pivotal role in glucose metabolism, energy homeostasis, and immune signaling, understanding how insufficient sleep affects global transcriptomic responses in skeletal muscle is of significant interest. In a randomized crossover design, skeletal muscle biopsies were collected from healthy postmenopausal women following four nights of habitual or restricted sleep (40% reduction). RNA-seq was performed on 7 paired samples and analyzed using differential expression (DE), gene correlation, pathway enrichment, and transcription factor motif analysis. Global DE analysis revealed modest transcriptomic shifts, with 9 genes consistently altered across multiple DE methods. Gene set enrichment analysis showed upregulation of oxidative phosphorylation and myogenesis pathways and downregulation of immune and inflammatory signaling during sleep restriction. Differential correlation analysis identified substantial reorganization in gene co-expression networks, particularly within RNA degradation and ribosomal pathways. Transcription factor and motif analyses suggested YY1 as a possible key mediator of transcriptional reprogramming during sleep restriction. Motif analysis confirmed enrichment of YY1 binding sites among differentially correlated genes, further implicating its role in linking circadian disruption, metabolic stress, and immune modulation. Sleep restriction for 4-nights triggers subtle but biologically meaningful changes in skeletal muscle transcriptomes. The simultaneous upregulation of mitochondrial and structural genes, alongside downregulation of immune-related genes, reflects a complex adaptive response. YY1 appears to be a central regulatory node linking sleep loss to muscle dysfunction, with implications for metabolic resilience, inflammation, and tissue repair.

Keywords:  Sleep restriction; correlation analysis; motif analysis; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.1152/physiolgenomics.00269.2025
Autophagy. 2026 Mar 30. 1-3

Dual pathways of TFEB activation under lysosomal stress: ATG conjugation-dependent and -independent modes.

Takayuki Shima, Shuhei Nakamura.

  TFEB (transcription factor EB) regulates the expression of autophagy and lysosomal genes, is activated by various cellular stresses, and plays a key role in maintaining cellular homeostasis. Recent work demonstrates that TFEB is activated during lysosomal damage through two distinct mechanisms: ATG conjugation-dependent and -independent. TFEB activation proceeds sequentially through two modes. In the early ATG conjugation-independent mode (Mode I), APEX1 interacts with TFEB in the nucleus, maintaining its transcriptional activity and protein stability. In the later ATG conjugation-dependent mode (Mode II), CCT7 and TRIP6 translocate to lysosomes and interact with TFEB, modulating its phosphorylation and nuclear localization. Moreover, TFEB regulation induced by other cellular stresses-such as oxidative stress, proteasome inhibition, mitochondrial damage, and DNA damage-also involves either Mode I or Mode II. Our findings provide new insights into a unified understanding of TFEB regulation under diverse cellular stress conditions.

Keywords:  Damage; TFEB; lysosome; mitochondria; organelle

DOI:  https://doi.org/10.1080/15548627.2026.2642336
RNA. 2026 Apr 01. pii: rna.080820.125. [Epub ahead of print]

ADARs mediate distinct RNA editing activity and gene regulation in the Caenorhabditis elegans germline.

Emily A Erdmann, Leanne H Kelley, Heather A Hundley.

  Tissues rely on unique landscapes of gene regulation to allow the organism to correctly develop, function, and respond to changes. One component of these gene regulatory networks is RNA Binding Proteins (RBPs) which bind and modify RNA molecules leading to changes in the cellular fate of transcripts. The Adenosine DeAminase acting on RNA (ADAR) family of RBPs modify RNAs by catalyzing the deamination of adenosine (A) to inosine (I), known as A-to-I RNA editing. Prompted by recent evidence that ADARs play important roles in germline biology, we profiled editing activity of the A-to-I editing enzyme ADR-2 on transcripts in the Caenorhabditis elegans germline. These analyses revealed that many germline editing events are distinct from editing events in other tissues; however, the previously described role of the inactive deaminase ADR-1 in regulating editing activity by ADR-2 is conserved in the germline. We find that complete loss or misregulation of editing has little effect on the expression of edited transcripts within the germline; however, loss of ADARs results in the misexpression of several unedited germline transcripts. Intriguingly, further investigation suggests that these expression changes are buffered at the translational level. In all, the results of this study suggest that ADARs show unique activity in the C. elegans germline and that compensatory mechanisms exist to lessen the immediate consequences of loss of ADAR function within the germline.

Keywords:  ADR-1; ADR-2; inosine; post-transcriptional; translational regulation

DOI:  https://doi.org/10.1261/rna.080820.125