bims-musmir 2026-01-11 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–01–11
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Exercise-induced antioxidant programing in oxidative muscle: A critical IL1β-NBR1-p62 axis.
Mechanism-based nutritional approaches in cancer cachexia.
Age-Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics.
The Liver Clock Tunes Transcriptional Rhythms in Skeletal Muscle to Regulate Mitochondrial Function.
mRNA transcription in skeletal muscle drives growth and determines nuclear accretion.
The Potential of MicroRNAs in the Context of Sarcopenic Obesity.
Temporal Multi-Omic Analysis Uncovers Sex-Biased Molecular Programs Underlying Skeletal Muscle Adaptation to Endurance Training.
IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies.
Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle.
Immune Cell Mitochondrial Phenotypes Are Largely Preserved in Mitochondrial Diseases and Do Not Reflect Disease Severity.
Overactive PDGFRα and PDGFRβ promote distinct yet overlapping phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving drastic muscle growth.
FTO promotes skeletal muscle differentiation and regeneration by regulating m 6 A-modified c-Myc.
Local mitochondrial physiology defined by mtDNA quality guides purifying selection.
Changes in body composition, muscle function, and muscle insulin sensitivity induced by obesity and bariatric surgery: Implications for sarcopenic obesity.
miR-199a Knockdown Alleviates Insulin Resistance and Inflammation by Targeting DDIT4 via the PI3K/AKT Pathway in vitro and in vivo.

Am J Physiol Regul Integr Comp Physiol. 2026 Jan 09.

Exercise-induced antioxidant programing in oxidative muscle: A critical IL1β-NBR1-p62 axis.

Ruqaiza Muhyudin, Nicholas P Greene.



Keywords:  fiber type dependant; glycolytic muscle; oxidative stress

DOI:  https://doi.org/10.1152/ajpregu.00333.2025
Curr Opin Clin Nutr Metab Care. 2026 Jan 07.

Mechanism-based nutritional approaches in cancer cachexia.

Emma Elisabeth Cappellato, Paola Costelli, Fabio Penna.

   PURPOSE OF REVIEW: Cancer cachexia is a complex multiorgan wasting syndrome that negatively impacts on cancer patient's survival and quality of life. Standard nutritional support is considered insufficient to counteract cachexia, and no approved nutritional approach or standard of care for cachexia exists so far. This review highlights recent reports focused on nutrition, aimed at sparing skeletal muscle and targeting molecular pathways underlying cachexia with specific supplements.
RECENT FINDINGS: In animal models of cancer cachexia, branched-chain amino acids (BCAAs) help restore skeletal muscle proteostasis. In combination with the alanine dipeptide, with strong proteinogenic potential, BCAAs enhance anabolic signaling and suppress proteolysis via mTOR. α-ketoisocaproate exerts additional protective effects against muscle loss by targeting the Akt/FoxO3a and myostatin signaling. Methionine and the derivative SAM improve muscle status via epigenetic control and REDD1 suppression. L-carnitine shows multitarget functions, including muscle proteostasis control, inflammation attenuation, and reduced muscle fibrosis. Omega-3 polyunsaturated fatty acids show anti-inflammatory properties, improve the nutritional status, and prevent adipose tissue browning.
SUMMARY: Overall, recent findings in preclinical and partly in clinical studies indicate that nutrient-based interventions target complementary cancer cachexia alterations. It is likely that combinatorial approaches, integrating several specific nutrients, will provide an effective base for managing cancer patients during the long journey of the disease, building future interventions against cancer cachexia.

Keywords:  cancer cachexia; mechanisms; muscle wasting; nutritional support

DOI:  https://doi.org/10.1097/MCO.0000000000001207
Aging Cell. 2026 Jan;25(1): e70355

Age-Associated Dysregulation of Postsynaptic Mitochondria Perturbs Reinnervation Kinetics.

Steve D Guzman, Paula M Fraczek, Klimentini Itsani, Esraa K Furati, Devin Juros, Grace Kenney, Gregorio Valdez, Joe V Chakkalakal, Carlos A Aguilar.

Age-associated degeneration of neuromuscular junctions (NMJs) contributes to sarcopenia and motor function decline, yet the mechanisms that drive this dysfunction in aging remain poorly defined. Here, we demonstrate that postsynaptic mitochondria are significantly diminished in quantity in old-aged skeletal muscle, correlating with increased denervation and delayed reinnervation following nerve injury. Single-nucleus RNA sequencing before and after sciatic nerve crush from young and old-aged muscles further revealed that sub-synaptic myonuclei in old-aged muscle exhibit attenuated expression of mitochondrial gene programs, including oxidative phosphorylation, biogenesis, and import. To test whether these deficits are causal, we developed a muscle-specific CRISPR genome editing approach and targeted CHCHD2 and CHCHD10-two nuclear-encoded mitochondrial proteins that localize to the intermembrane space and interact with the mitochondrial contact site and cristae organizing system. CRISPR knockout of CHCHD2 and CHCHD10 in young muscle recapitulated old-aged muscle phenotypes, including mitochondrial disorganization, reduced ATP production, NMJ fragmentation, and delayed reinnervation. Transcriptional profiling of sub-synaptic myonuclei using single-nuclei RNA sequencing from CHCHD2 and CHCHD10 knockout muscles revealed impairments in activation of mitochondrial remodeling programs and elevated stress signatures when compared with controls. These findings establish a critical role for postsynaptic mitochondrial integrity in sustaining NMJ stability and regenerative capacity and identify CHCH domain-containing proteins as key regulators of postsynaptic mitochondrial function during aging and injury.

DOI: https://doi.org/10.1111/acel.70355
J Biol Rhythms. 2026 Jan 04. 7487304251386926

The Liver Clock Tunes Transcriptional Rhythms in Skeletal Muscle to Regulate Mitochondrial Function.

Valentina Sica, Tomoki Sato, Ioannis Tsialtas, Sophia Hernandez, Siwei Chen, Pierre Baldi, Pura Muñoz-Cánoves, Paolo Sassone-Corsi, Kevin B Koronowski, Jacob G Smith.

  Circadian clocks present throughout the brain and body coordinate diverse physiological processes to support daily homeostasis, yet the specific interorgan signaling axes involved are not well defined. We previously demonstrated that the skeletal muscle clock controls transcript oscillations of genes involved in fatty acid metabolism in the liver, yet the impact of the liver clock on the muscle remained unknown. Here, we use male hepatocyte-specific Bmal1 KO mice (Bmal1hep-/-) to reveal that approximately one-third of transcript rhythms in skeletal muscle are influenced by the liver clock in vivo. Treatment of myotubes with serum harvested from Bmal1hep-/- mice inhibits expression of genes involved in metabolic pathways, including oxidative phosphorylation. Only small transcriptional changes were induced by liver clock-driven endocrine communication in vitro, leading us to surmise that the liver clock acts to fine-tune metabolic gene expression in muscle. Consistent with functional tuning, treatment of myotubes with serum collected from Bmal1hep-/- mice during the dark phase lowers mitochondrial ATP production compared with serum from wild-type mice. Overall, our results reveal communication between the liver clock and skeletal muscle, uncovering a bidirectional endocrine communication pathway that may contribute to the metabolic phenotypes of circadian disruption.

Keywords:  Bmal1; circadian clocks; circadian rhythms; clock communication; interorgan crosstalk; liver metabolism; mitochondria; muscle-liver axis; peripheral clocks; skeletal muscle

DOI:  https://doi.org/10.1177/07487304251386926
bioRxiv. 2025 Dec 29. pii: 2025.12.29.696842. [Epub ahead of print]

mRNA transcription in skeletal muscle drives growth and determines nuclear accretion.

Fabian Montecino-Morales, Cristofer Calvo, Casey O Swoboda, Alena Bruening, Alyssa A W Cramer, Xin Lin, Jennifer L Martin, Ramzi J Khairallah, Yarui Diao, Vikram Prasad, Douglas P Millay.

Multinucleation of skeletal muscle cells (myofibers) is a determinant of size and fundamental for function. While it is established that myofibers need to accrue adequate numbers of nuclei for optimal growth, the molecular circuitry linking myonuclei to growth and why myofibers need additional nuclei remains unknown. We found that growth is still possible after restriction of nuclear content in myofibers and this was associated with increased levels of RNA Polymerase II ( Polr2a ) leading to elevated mRNA content. Through development of a genetic mouse model where endogenous Polr2a is upregulated in myofibers, we established that increased transcriptional output is sufficient to drive functional growth of myofibers. Notably, we discovered that Polr2a overexpression curtails the need for additional nuclei for myofiber growth. These data reveal a previously neglected driver of functional muscle growth and highlight that increasing Polr2a -mediated transcription from the vast numbers of nuclei within myofibers could be leveraged to combat muscle wasting conditions.

DOI: https://doi.org/10.64898/2025.12.29.696842
Physiol Res. 2025 Dec 31. 74(Suppl 1): S65-S75

The Potential of MicroRNAs in the Context of Sarcopenic Obesity.

N Chobolová, Z Švagera, D Stejskal, M Bužga.

Sarcopenic obesity (SO) is a complex pathological condition characterized by the simultaneous presence of excessive adipose tissue and the loss of muscle mass and strength. This combination leads to an increased risk of metabolic, cardiovascular, and functional complications. In recent years, there has been growing interest in the use of microRNAs (miRNA) as biomarkers capable of detecting early changes in body composition and predicting the progression of SO. MiRNAs are small noncoding RNA molecules that play a key role in regulating gene expression and cellular pathways related to inflammation, metabolism, and muscle trophism. This article summarizes current knowledge about miRNAs expression in patients with sarcopenic obesity, their regulatory functions, and their potential use in diagnostics and therapy. Key words microRNA " Sarcopenic obesity " miRNA " Biomarkers " Muscle atrophy " Inflammation.
bioRxiv. 2025 Dec 27. pii: 2025.12.26.696612. [Epub ahead of print]

Temporal Multi-Omic Analysis Uncovers Sex-Biased Molecular Programs Underlying Skeletal Muscle Adaptation to Endurance Training.

MoTrPAC study group

Background: Exercise training is known to benefit health and reduce disease risk. While skeletal muscle adaptations are fundamental to many of the health benefits of exercise training, the common and sex-specific molecular regulators that mediate these adaptations remain to be fully elucidated.
Methods: To this end, we leveraged skeletal muscle multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), where 6 month-old male and female rats endurance trained for 1, 2, 4, or 8 weeks. Our objective was to identify shared and sex-specific multi-omic molecular responses to endurance training in skeletal muscle, and relate them to phenotypic adaptations.
Results: We identified largely sexually-conserved transcriptomic and proteomic pathway enrichments in the gastrocnemius , which correlated with skeletal muscle responses from a published exercise study in humans. We uncovered sex-consistent post-translational modifications, including decreased oxidation of MYH2 and deacetylation of the β-oxidation enzyme HADHA. Pathway enrichment analyses revealed sex-specific remodeling across the acetylome, redox proteome, and phosphoproteome; females decreased mitochondrial protein cysteine oxidation and increased mitochondrial cristae proteins, indicative of enhanced redox buffering and mitochondrial efficiency. Despite decreases in cysteine oxidation of key mitochondrial proteins, females displayed increases in the cysteine oxidation of proteins involved in glucose catabolism relative to males after 8 weeks of training, suggestive of sex-biased subcellular reactive oxygen species generation. Males demonstrated earlier induction of mitochondrial transcripts and predicted activation of mTOR. Although the increase in mitochondrial protein abundance was more modest in males, there was greater oxidation of mitochondrial proteins in response to training compared to females.
Conclusions: This work shows a large portion of the adaptive response to endurance training in skeletal muscle is shared between females and males, while there are distinct and nuanced sex-specific adaptations that are evident, particularly at the level of post-translational regulation.

DOI: https://doi.org/10.64898/2025.12.26.696612
JCI Insight. 2026 Jan 06. pii: e183247. [Epub ahead of print]

IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies.

Wen Gu, Nicole Wilkinson, Carine Fillebeen, Darren Blackburn, Korin Sahinyan, Eric Bonneil, Tao Zhao, Zhi Luo, Vahab Soleimani, Vincent Richard, Christoph H Borchers, Albert Koulman, Benjamin Jenkins, Bernhard Michalke, Hans Zischka, Judith Sailer, Vivek Venkataramani, Othon Iliopoulos, Gary Sweeney, Kostas Pantopoulos.

  Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2α (HIF2α) mRNA, which increases renal erythropoietin production. Here we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet-induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.

Keywords:  Diabetes; Glucose metabolism; Hepatology; Metabolism; Proteomics

DOI:  https://doi.org/10.1172/jci.insight.183247
Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2423340122

Targeting C1q signaling in fibro-adipogenic progenitors prevents regenerative fibrosis of aged muscle.

Abhijnya Kanugovi, Paola Aguiari, Rachel Choi, Soochi Kim, Di Wu, Antoine De Morree, Summer Bui, Richard Lam, Stefano Biressi, Ling Liu, Thomas A Rando.

  Skeletal muscle fibrosis, as occurs with age, in response to injury, or in the setting of degenerative diseases, results in impairments of muscle regeneration and function. Fibro-adipogenic progenitors (FAPs), a distinct population of muscle-resident mesenchymal progenitor cells that reside in the muscle interstitium, play a crucial role in normal muscle regeneration by supporting muscle stem cell proliferation. However, in pathological conditions such as severe or recurrent muscle injury, FAPs can aberrantly differentiate into fibrogenic cells, resulting in excessive deposition of extracellular matrix and fibrosis. In this study, we explore the molecular regulation of FAP differentiation along the fibrogenic lineage to gain insights into the mechanisms of fibrosis in aged muscle in response to injury. Our findings reveal that aging is associated with an increased expression of the complement component 1q (C1q) in muscle-resident macrophages and elevated expression of the complement proteins C1r and C1s in FAPs. Exposure of proliferating FAPs to C1q results in the activation of the Wnt signaling pathway, elevated expression of collagen genes, and FAP fibrogenic differentiation, leading to increased tissue fibrosis. We demonstrate that either pharmacological inhibition of the complement pathway or genetic ablation of C1s in FAPs in aged mice reduces fibrogenic differentiation of FAPs by suppressing Wnt signaling. This reduction in FAP differentiation attenuates the fibrotic response to injury in aged animals as well as in a mouse model of muscular dystrophy. Our study supports the inhibition of complement signaling as a potential therapeutic strategy for mitigating fibrosis in skeletal muscle injury or degeneration.

Keywords:  aging; complement, C1q; fibro-adipogenic progenitors; fibrosis; muscular dystrophy

DOI:  https://doi.org/10.1073/pnas.2423340122
Neurol Genet. 2026 Feb;12(1): e200343

Immune Cell Mitochondrial Phenotypes Are Largely Preserved in Mitochondrial Diseases and Do Not Reflect Disease Severity.

Cynthia C Liu, Mangesh Kurade, Anna S Monzel, Catherine Kelly, Robert-Paul Juster, Caroline Trumpff, Michio Hirano, Martin Picard.

Background and Objectives: The aim of this study was to profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how these phenotypes relate to disease manifestations or biomarkers.
Methods: We profiled mitochondrial content and oxidative phosphorylation (OxPhos) enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A > G, n = 23; single, large-scale mitochondrial DNA (mtDNA) deletions, n = 14) and 68 healthy women and men from the Mitochondrial Stress, Brain Imaging, and Epigenetics study.
Results: We first confirmed and quantified robust cell type differences in mitochondrial content; activities of OxPhos complexes I, II, and IV; and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity was consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. MitoD biomarkers growth differentiation factor 15 and fibroblast growth factor 21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state with those in the afternoon/fed state after a stressful experience, we report significant time-dependent changes in mitochondrial biology over hours.
Conclusions: Overall, these results demonstrate that the dynamic and cell type-specific mitochondrial phenotypes are preserved in MitoD and are generally unrelated to symptom severity.

DOI: https://doi.org/10.1212/NXG.0000000000200343
bioRxiv. 2026 Jan 02. pii: 2026.01.02.697406. [Epub ahead of print]

Overactive PDGFRα and PDGFRβ promote distinct yet overlapping phenotypes of skeletal muscle fibrosis and stiffness, with PDGFRβ also driving drastic muscle growth.

Mariola Gimla, Szczepan Olszewski, Jacob L Brown, Christiana Raymond-Pope, Sandra Rigsby, Frederick F Peelor, Hae Ryong Kwon, Longbiao Yao, Lorin E Olson, Jordan D Fuqua, Benjamin F Miller.

Background: Fibrosis accumulates in skeletal muscle over time and leads to greater muscle rigidity, stiffness, and increased risk of injuries. However, investigations of experimental models to study the mechanisms through which muscle fibrosis occurs are often confounded by injury or disease. The contribution of platelet-derived growth factor receptors alpha and beta (PDGFRα or PDGFRβ) to muscle fibrosis is yet to be clarified. We hypothesized that both receptors would promote ECM deposition and fibrosis, causing muscle stiffening and weakness, with sex-specific differences arising due to hormonal influences on receptors. Methods: To test this hypothesis, we used a mouse model with inducible overactive PDGFRα or PDGFRβ signaling and assessed various indicators of muscle function, metabolism, motor coordination, exercise capacity, collagen deposition, and muscle stiffness. Results: Overactive PDGFRα led to more collagen deposition, increased collagen crosslinking, and higher AGE/LOX protein levels, all of which correlated with greater muscle stiffness compared to CON. Overactive PDGFRβ resulted in greater muscle mass and lower fat mass, and had higher collagen deposition in female mice compared to CON. There were also sex-specific differences with fibrotic remodeling, muscle stiffness, and muscle size in response to overactive PDGFRα and PDGFRβ signaling. Conclusion: These findings establish PDGFRα and PDGFRβ signaling as distinct regulators of muscle remodeling and establish overactive PDGFRα as a mouse model to study skeletal muscle fibrosis in the absence of other confounding variables.

DOI: https://doi.org/10.64898/2026.01.02.697406
bioRxiv. 2025 Dec 30. pii: 2025.12.30.696954. [Epub ahead of print]

FTO promotes skeletal muscle differentiation and regeneration by regulating m 6 A-modified c-Myc.

Paromita Dey, Bijan K Dey.

Recent studies have revealed the crucial role of m 6 A RNA methylation in various myogenic processes. However, the specific function and underlying molecular mechanisms of this modification in vivo during skeletal muscle differentiation and regeneration remain unclear. In this study, we examine the role and mechanism of the m 6 A RNA demethylase fat mass and obesity-associated protein (FTO) in skeletal muscle differentiation and regeneration in mice. Our findings demonstrate that FTO is upregulated during both skeletal muscle differentiation and regeneration and is essential for these key myogenic processes. We show that exogenous FTO expression in primary myoblasts enhances differentiation, whereas FTO knockdown inhibits it. Additionally, FTO knockout in mouse muscle stem cells impairs muscle regeneration. FTO promotes skeletal muscle differentiation and regeneration by directly targeting and regulating m 6 A-modified c-Myc, a well-known repressor of myogenesis. The IGF2BP2 reader protein recognizes m 6 A-modified c-Myc in undifferentiated myoblasts and stabilizes it. As FTO levels increase during myoblast differentiation, m 6 A levels on c-Myc decrease. This reduction prevents IGF2BP2 from binding to c-Myc, thereby destabilizing c-Myc levels and promoting differentiation. Overall, our findings underscore the significance of the novel FTO/c-Myc/IGF2BP2 axis in skeletal muscle differentiation and regeneration.

DOI: https://doi.org/10.64898/2025.12.30.696954
PLoS Genet. 2026 Jan 09. 22(1): e1011836

Local mitochondrial physiology defined by mtDNA quality guides purifying selection.

Felix Thoma, Johannes Hagen, Romina Rathberger, Francesco Padovani, David Hörl, Kurt M Schmoller, Christof Osman.

The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain and ATP synthase. Mutations in these genes impair oxidative phosphorylation, compromise mitochondrial ATP production and cellular energy supply, and can cause mitochondrial diseases. These consequences highlight the importance of mtDNA quality control (mtDNA-QC), the process by which cells selectively maintain intact mtDNA to preserve respiratory function. Here, we developed a high-throughput flow cytometry assay for Saccharomyces cerevisiae to track mtDNA segregation in cell populations derived from heteroplasmic zygotes, in which wild-type (WT) mtDNA is fluorescently labeled and mutant mtDNA remains unlabeled. Using this approach, we observe purifying selection against mtDNA lacking subunits of complex III (COB), complex IV (COX2) or the ATP synthase (ATP6), under fermentative conditions that do not require respiratory activity. By integrating cytometric data with growth assays, qPCR-based mtDNA copy-number measurements, and simulations, we find that the decline of mtDNAΔatp6 in populations derived from heteroplasmic zygotes is largely explained by the combination of its reduced mtDNA copy number-biasing zygotes toward higher contributions of intact mtDNA-and the proliferative disadvantage of cells carrying this variant. In contrast, the loss of mtDNAΔcob and mtDNAΔcox2 cannot be explained by growth defects and copy-number asymmetries alone, indicating an additional intracellular selection against these mutant genomes when intact mtDNA is present. In heteroplasmic cells containing both intact and mutant mtDNA, fluorescent reporters revealed local reductions in ATP levels and membrane potential ([Formula: see text]) near mutant genomes, indicating spatial heterogeneity in mitochondrial physiology that reflects local mtDNA quality. Disruption of the respiratory chain by deletion of nuclear-encoded subunits (RIP1, COX4) abolished these physiological gradients and impaired mtDNA-QC, suggesting that local bioenergetic differences are required for selective recognition. Together, our findings support a model in which yeast cells assess local respiratory function as a proxy for mtDNA integrity, enabling intracellular selection for functional mitochondrial genomes.

DOI: https://doi.org/10.1371/journal.pgen.1011836
Clin Nutr. 2025 Dec 11. pii: S0261-5614(25)00326-7. [Epub ahead of print]56 106547

Changes in body composition, muscle function, and muscle insulin sensitivity induced by obesity and bariatric surgery: Implications for sarcopenic obesity.

Laura Orioli, Jean-Paul Thissen, Audrey Loumaye.

  Sarcopenic obesity, defined by the coexistence of excess adiposity and sarcopenia, represents an emerging clinical concern. Bariatric surgery, an effective treatment option for obesity, induces muscle mass loss, raising concerns about the potential development or worsening of sarcopenia. However, bariatric surgery improves body composition, notably the muscle-to-fat ratio, and muscle function, suggesting that the overall risk of sarcopenic obesity may actually decrease after bariatric surgery. The mechanisms underlying this paradox are not well characterized. Obesity profoundly alters skeletal muscle homeostasis, leading to insulin and anabolic resistance that contribute to type 2 diabetes and sarcopenia well before old age. In contrast, bariatric surgery, despite inducing muscle mass loss, improves or even reverses obesity-related alterations in muscle phenotype and oxidative metabolism, while reducing myosteatosis, inflammation and insulin resistance, thereby promoting overall improved muscle metabolic and functional health. This review examines how obesity and bariatric surgery affect skeletal muscle mass, function and insulin sensitivity, and discusses the implications of these alterations for the development, worsening, or remission of sarcopenic obesity after bariatric surgery.

Keywords:  Fat-free mass; Insulin resistance; Muscle strength; Myokines; Sarcopenia; Sarcopenic obesity

DOI:  https://doi.org/10.1016/j.clnu.2025.106547
Diabetes Metab Syndr Obes. 2025 ;18 4931-4942

miR-199a Knockdown Alleviates Insulin Resistance and Inflammation by Targeting DDIT4 via the PI3K/AKT Pathway in vitro and in vivo.

Ya-Wei Cai, Ling-Jia Tang, Yao Zhu, Sen-Sen Ye, Tong-En Chen.

   Background: Insulin resistance (IR) is a pivotal pathological feature in the development of type 2 diabetes mellitus (T2DM). MicroRNA-199a (miR-199a) has been implicated in various metabolic disorders, but its precise role and mechanism in hepatic IR remain largely unexplored. This study aimed to investigate the role of miR-199a in IR and inflammation and to determine whether its effects are mediated through DDIT4 and the PI3K/AKT pathway.
Methods: An in vitro IR model was established in HepG2 cells using palmitic acid, and an in vivo T2DM model was induced in mice using a high-fat diet combined with streptozotocin injection. Functional assays, including glucose uptake and ELISA, were employed to assess metabolic and inflammatory responses. The interaction between miR-199a and its putative target, DDIT4, was validated by luciferase reporter and RNA immunoprecipitation assays. Key proteins in the PI3K/AKT signaling pathway were analyzed by Western blotting.
Results: We found that miR-199a was significantly upregulated, while DDIT4 was downregulated in both IR HepG2 cells and diabetic mice. Mechanistically, we identified DDIT4 as a direct target of miR-199a. Knockdown of miR-199a ameliorated insulin resistance and suppressed inflammation, whereas concomitant depletion of DDIT4 abolished these protective effects. Furthermore, miR-199a inhibition activated the PI3K/AKT pathway, as evidenced by increased phosphorylation of PI3K, AKT, and AS160, and decreased phosphorylation of FOXO1. These signaling changes were also dependent on DDIT4. In vivo, inhibition of miR-199a improved glucose homeostasis, attenuated systemic inflammation, and activated pancreatic PI3K/AKT signaling in T2DM mice.
Conclusion: Our findings reveal a novel miR-199a/DDIT4 axis that regulates insulin sensitivity and inflammation via the PI3K/AKT pathway, suggesting miR-199a as a potential therapeutic target for T2DM.

Keywords:  DDIT4; PI3K/AKT; insulin resistance; microRNA-199a; type 2 diabetes mellitus

DOI:  https://doi.org/10.2147/DMSO.S549884