bims-musmir 2026-01-18 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–01–18
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Ablation of Tumor-Derived IGFBP-3 Attenuates Cancer-Associated Skeletal Muscle Wasting in Murine Pancreatic Cancer.
Separating food intake-dependent and -independent effects in cancer cachexia.
Sex differences in cachexia outcomes and branched-chain amino acid metabolism following chemotherapy in aged mice.
Is Ferroptosis the Mechanistic Bridge Connecting Iron Dysregulation to Muscle Wasting and Functional Decline in Aging?
Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer.
TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.
Acyl-CoA Binding Protein in White and Brown Adipose Tissue Is Dispensable for Systemic Energy Metabolism in Mice.
Skeletal muscle-kidney crosstalk in a cohort of critical illness survivors.
The Ubiquitin-Proteasome Pathway Mediates Selective Degradation of Unloaded Argonaute Proteins in C. elegans.
Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.
Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.

Am J Physiol Cell Physiol. 2026 Jan 12.

Ablation of Tumor-Derived IGFBP-3 Attenuates Cancer-Associated Skeletal Muscle Wasting in Murine Pancreatic Cancer.

Zachary R Sechrist, Daniel J Belcher, Nidhi R Patel, Zoe J Pittman, Edward M Schwarz, Calvin L Cole.

  Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths, and its incidence is expected to rise. Skeletal muscle wasting (SMW) is a debilitating co-morbidity of PDAC with unknown etiology. Previously our lab demonstrated that systemic increases in Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) is associated with SMW and pathologic myocellular lipid accumulation in an orthotopic murine model of PDAC (Ptf1atm1-cre/+;Krastm4Tyj;Muc1-/-(KCKO)). Here we show that PDAC tumor cells secrete high levels of IGFBP-3 and that genetic ablation of IGFBP-3 in the KCKO and Ptf1atm1(cre)Cvw/WT;Krastm4Tyj/WT;Trp53tm5Tyj/tm5Tyj (KP2) orthotopic models of PDAC increases survival by at least 30 days in both models without affecting tumor progression. Mice with IGFBP-3-/- tumors lost 10- and 3-fold less appendicular lean mass, and experienced a 5- and 6-fold decrease in myocellular lipid accumulation vs mice with parental KCKO and KP2 tumors, respectively, at failure to thrive endpoints. Gene expression studies demonstrated increases in the ubiquitin proteasome pathway (fbxo32 and trim32), autophagy (ULK1 and LC3bII), and TGF-βR signaling (tgfβr1 and FoxO1) in skeletal muscle of mice inoculated with parental PDAC tumors, which was absent in mice with IGFBP-3-/- tumors. In vitro studies confirmed a role for IGFBP-3 in stimulating TGF-β receptors and regulating SMAD3 nuclear localization. Moreover, IGFBP-3 deletion in tumor cells and small molecule inhibition of TGF-βR1/2 attenuated myotube wasting. Collectively, these results suggest that PDAC derived IGFBP-3 promotes SMW via non-canonical binding of TGF-βRs, warranting formal investigation of IGFBP-3 as a potential therapeutic target for PDAC-related SMW through a novel pathway.

Keywords:  Cancer Cachexia; IGFBP-3; PDAC; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpcell.00421.2025
bioRxiv. 2026 Jan 06. pii: 2025.04.24.650538. [Epub ahead of print]

Separating food intake-dependent and -independent effects in cancer cachexia.

Yanshan Liang, Young-Yon Kwon, Sheng Hui.

Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle tissues, with diminished food intake due to anorexia commonly cited as a cause. However, to what extent reduced food intake drives these symptoms and other cachexia phenotypes, such as fatigue, remains generally unclear in preclinical models and patient populations. Here we demonstrate the critical need to address this question in cancer cachexia research. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and wasting of fat and muscle, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing fatigue. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.

DOI: https://doi.org/10.1101/2025.04.24.650538
PLoS One. 2026 ;21(1): e0340647

Sex differences in cachexia outcomes and branched-chain amino acid metabolism following chemotherapy in aged mice.

Stephen Mora, Gagandeep Mann, Olasunkanmi A J Adegoke.

Cachexia is a complex muscle wasting syndrome that affects the majority of hospitalized cancer patients receiving chemotherapy. It is often unresponsive to nutritional interventions, including provision of branched-chain amino acids (BCAAs: leucine, isoleucine and valine). BCAAs are anabolic for skeletal muscle. We wondered whether their ineffectiveness in managing cachexia might be related to altered metabolism of these amino acids, a subject that has received minimal attention. Because estrogen limits BCAA catabolism, we hypothesized that the effects of chemotherapy on cachexia in old mice would be worse in males compared to females, and that this would be related to greater tissue release of the BCAAs in males. To better reflect the age population for which cachexia is an issue, we treated aged male and female mice (18 ± 2 months) with the chemotherapy drug cocktail FOLFIRI (50 mg/kg 5-fluorouracil (5FU), 90 mg/kg Leucovorin, and 24 mg/kg CPT11) or vehicle twice per week for 6 weeks. This cocktail is used in treating colon cancer. Metabolism and concentrations of the BCAAs and their metabolites were measured in plasma and tissues. There was a main effect of chemotherapy, reflected in reduced body weight, skeletal muscle, myofibrillar protein content, anabolic signalling and protein synthesis. In response to chemotherapy, males showed worsened outcomes for skeletal muscle weight and ubiquitinated proteins; they also had higher total plasma BCAAs but reduced muscle BCAAs. There was a main effect of chemotherapy in reducing the expression of the BCAA transporter LAT1. In response to chemotherapy, gastrocnemius muscle of males but not females had reduced inhibitory phosphorylation of BCKD-E1αser293, corresponding with increased activity of this enzyme. Chemotherapy reduced muscle and liver ketoacids of the BCAAs only in females. These data suggest that sex differences in BCAA catabolism may be linked to the severity of chemotherapy-induced muscle damage and interventions against cachexia need to take this into account.

DOI: https://doi.org/10.1371/journal.pone.0340647
Aging Cell. 2026 Feb;25(2): e70367

Is Ferroptosis the Mechanistic Bridge Connecting Iron Dysregulation to Muscle Wasting and Functional Decline in Aging?

Rola S Zeidan, Simon Reinhard, Anna Picca, Emanuele Marzetti, Christiaan Leeuwenburgh, James F Collins, Stephen D Anton.

  Age-related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron-dependent, lipid peroxidation-driven cell death, as a compelling but underexplored contributor to age-related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established. Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro-ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis-specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.

Keywords:  Ferroptosis; iron; older adults; physical function; skeletal muscle

DOI:  https://doi.org/10.1111/acel.70367
Nat Metab. 2026 Jan 15.

Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer.

Pauline Morigny, Michaela Vondrackova, Honglei Ji, Kristyna Brejchova, Monika Krakovkova, Konstantinos Makris, Radka Trubacova, Tuna F Samanci, Doris Kaltenecker, Su-Ping Ng, Vignesh Karthikaisamy, Sophia E Chrysostomou, Anna Bidovec, Mariana Ponce-de-Leon, Tanja Krauss, Claudine Seeliger, Olga Prokopchuk, Marc E Martignoni, Melina Claussnitzer, Hans Hauner, Martina Schweiger, Laure B Bindels, Mauricio Berriel Diaz, Stephan Herzig, Dominik Lutter, Ondrej Kuda, Maria Rohm.

Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour-host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting.

DOI: https://doi.org/10.1038/s42255-025-01434-3
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00023-7. [Epub ahead of print]

TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.

Yixiao Xu, Yishun Gong, Jiafa Zhong, Binghong Gao.

   OBJECTIVE: Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.
METHODS: A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H2O2 emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.
RESULTS: In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.
CONCLUSION: TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.

Keywords:  TRPV1; active heat acclimation; mitochondrial turnover; oxidative phosphorylation; skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.015
Acta Physiol (Oxf). 2026 Feb;242(2): e70159

Acyl-CoA Binding Protein in White and Brown Adipose Tissue Is Dispensable for Systemic Energy Metabolism in Mice.

M F Nørremark, R Petersen, P M M Ruppert, E S Jul, T K Doktor, R Nielsen, J F Kappel, S Larsen, J W Kornfeld, S Mandrup, B S Andresen, J Havelund, D Neess, N J Færgeman.

   AIM: Acyl-CoA binding protein plays a vital role in lipid metabolism by mediating the intracellular flux and utilization of long-chain acyl-CoAs. We generated an adipocyte-wide ACBP knockout mouse and a brown adipose tissue-specific ACBP knockout mouse to investigate ACBP function in adipose tissue.
METHODS: Male mice with conditional targeting of the Acbp gene in adipose tissue (Adipoq-Acbp-/-) or brown adipose tissue (Ucp1-Acbp-/-) were generated by crossing Acbpflox/flox mice with transgenic mice expressing Cre recombinase under the control of the adiponectin (Adipoq-Cre) or uncoupling protein 1 (Ucp1-Cre) promoter, respectively. Systemic energy expenditure was assessed by indirect calorimetry. Body composition was examined using nuclear magnetic resonance. Primary brown and white preadipocytes were isolated to examine their ability to differentiate to mature adipocytes. Lipid composition of adipose tissues was examined by lipidomics. Global changes in gene expression in adipose tissues were examined by RNA sequencing. Tissue respiration was determined using high-resolution respirometry.
RESULTS: We demonstrate that loss of ACBP in adipose tissue does not affect body weight, fat and lean mass, food intake and systemic energy expenditure, even under cold stress. Global gene expression analysis shows only minor changes in gene expression, whereas lipidomic profiling reveals a subtle increase in acyl-carnitine levels in brown adipose tissue. Lipolytic activity in white adipose tissue as well as plasma glycerol, nonesterified fatty acid and triacylglycerol levels remained unaffected. In addition, no changes in mitochondrial respiration in BAT were observed.
CONCLUSION: Our findings suggest that ACBP is dispensable for adipose tissue function and systemic energy metabolism.

Keywords:  ACBP; acyl‐CoA; adipose tissue; energy expenditure; fatty acids

DOI:  https://doi.org/10.1111/apha.70159
PLoS One. 2026 ;21(1): e0339795

Skeletal muscle-kidney crosstalk in a cohort of critical illness survivors.

HCFMUSP COVID-19 Study Group

BACKGROUND: The skeletal muscles and kidneys are frequently affected during critical illness; however, their crosstalk remains poorly explored, especially in the long-term evolution. Therefore, we investigated the crosstalk between skeletal muscle and kidney function in COVID-19 survivors.
METHODS: A cross-sectional analysis of a prospective cohort study with survivors of moderate to severe COVID-19 hospitalization. Skeletal muscle assessments included handgrip strength, calf circumference, ultrasound-measured quadriceps thickness, and gait speed test. Sarcopenia was diagnosed by modified EWGSOP2 (low handgrip strength plus low ultrasound-measured quadriceps thickness). Kidney function was assessed by estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and urine sediment analysis. Abnormal kidney function was defined as an eGFR < 60 mL/min/1.73m2, albuminuria (≥30 mg/g), and/or leukocyturia or hematuria.
RESULTS: A total of 734 survivors (46% female, 43% ≥ 60 years, 35% with diabetes) were assessed 7 ± 2 months post-hospital discharge. Sarcopenia was diagnosed in 21.4% of the cohort. Positive significant associations with eGFR were observed for calf circumference (β = 0.42 ml/min/1.73m2, 95%CI: 0.06 to 0.78) and thicknesses (mm) of rectus femoris (β = 0.47, 95%CI: 0.01 to 0.94) and vastus intermedius (β = 0.55, 95%CI: 0.14 to 0.96). None of the skeletal muscle parameters were associated with UACR (mg/g). Survivors with sarcopenia had lower eGFR (‒5.8 ml/min/1.73m2, 95%CI: ‒10.8 to ‒0.9), but similar frequencies of low eGFR (24% vs. 18%; p = 0.137), albuminuria (27% vs. 31%; p = 0.434) and abnormal urine sediment (17% vs. 22%; p = 0.217) as compared to those without sarcopenia. Sarcopenia was not associated with higher odds of low eGFR, albuminuria, or abnormal urine sediment.
CONCLUSIONS: In survivors of moderate to severe COVID-19 hospitalization, skeletal muscle mass was associated with eGFR, whereas sarcopenia per se was not independently associated with poor kidney function. These findings suggest the existence of a skeletal muscle-kidney crosstalk in this population.

DOI: https://doi.org/10.1371/journal.pone.0339795
Genetics. 2026 Jan 13. pii: iyag007. [Epub ahead of print]

The Ubiquitin-Proteasome Pathway Mediates Selective Degradation of Unloaded Argonaute Proteins in C. elegans.

Jenny M Zhao, Dieu An H Nguyen, Diego Cervantes, Brandon Vong, Carolyn M Phillips.

Argonaute proteins are essential effectors of small RNA-mediated gene regulation, yet the extent to which their stability depends on small RNA loading remains poorly understood. In Caenorhabditis elegans, we systematically disrupted the small RNA binding capacity of multiple Argonaute proteins to assess their stability in the absence of small RNA partners. We found that while most Argonautes remain stable when unable to bind small RNAs, a subset, including PRG-1, HRDE-1, and PPW-2, exhibited markedly reduced protein levels. Focusing on the PIWI-clade Argonaute PRG-1, we show that its destabilization occurs post-translationally and is independent of mRNA expression or translational efficiency. Instead, unbound PRG-1 is targeted for degradation by the ubiquitin-proteasome system. Additionally, the failure to load piRNAs disrupts PRG-1 localization to perinuclear germ granules. We further identify the E3 ubiquitin ligase EEL-1 as a factor contributing to the degradation of unloaded PRG-1. These findings uncover a critical role for small RNA loading in maintaining the stability and localization of a subset of Argonaute proteins, and reveal a quality control mechanism that selectively eliminates unbound PRG-1 to preserve germline regulatory fidelity.

DOI: https://doi.org/10.1093/genetics/iyag007
Nat Cell Biol. 2026 Jan 12.

Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.

Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.

The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.

DOI: https://doi.org/10.1038/s41556-025-01854-z
BMB Rep. 2026 Jan 12. pii: 6696. [Epub ahead of print]

Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.

Hyun-Ji Ham, Jin-A Lee.

Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.
Nat Commun. 2026 Jan 15.

Inactive ryanodine receptors sustain lysosomal availability for autophagy by promoting ER-lysosomal contact site formation.

Tim Vervliet, Jens Loncke, Marko Sever, Karan Ahuja, Chris Van den Haute, Tomas Luyten, Grace E Stutzmann, Catherine Verfaillie, Tihomir Tomašič, Geert Bultynck.

Lysosomal and endoplasmic reticulum (ER) Ca2+ release mutually influence each other's functions. Recent work revealed that ER-located ryanodine receptor(s) (RyR(s)) Ca2+ release channels suppress autophagosome turnover by the lysosomes. In familial Alzheimer's disease, inhibiting RyR hyperactivity restored autophagic flux by normalizing lysosomal vacuolar H+-ATPase (vATPase) levels. However, the mechanisms by which RyRs control lysosomal function and how this involves the vATPase remain unknown. Here, we show that RyRs interact with the ATP6v0a1 subunit of the vATPase, contributing to ER-lysosomal contact site formation. This interaction suppresses RyR-mediated Ca²⁺ release, leading to reduced lysosomal exocytosis. Pharmacological inhibition of RyR activity mimics these effects on lysosomal exocytosis. Retaining lysosomes inside cells via RyR inhibition increases ER-lysosomal contact site formation, rendering lysosomes more available for autophagic flux. In summary, these findings establish RyR/ATP6v0a1 complexes as ER-lysosomal tethers that dynamically and Ca2+ dependently regulate the intracellular availability of lysosomes to participate in autophagic flux.

DOI: https://doi.org/10.1038/s41467-025-68054-z