bims-musmir 2025-11-02 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–11–02
seven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Nicotinamide nucleotide transhydrogenase dysfunction transcriptionally impacts mitochondrial β-oxidation and neuromuscular junction in M. Gastrocnemius of 24-day-old mice.
microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.
Molecular Framework of the Onset and Progression of Skeletal Muscle Aging.
Arsenic Exposure Alters Liver Metabolism and Accelerates Skeletal Muscle Atrophy in Female BALB/c Mice.
Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions.
Urolithin A promotes peripheral nerve regeneration via TFEB-mediated mitophagy and NLRP3 inflammasome suppression.
Impact of the Timing of Initial Anamorelin Administration in Advanced Gastrointestinal Cancer With Cancer Cachexia.

Int J Biol Macromol. 2025 Oct 28. pii: S0141-8130(25)09166-4. [Epub ahead of print]332(Pt 1): 148609

Nicotinamide nucleotide transhydrogenase dysfunction transcriptionally impacts mitochondrial β-oxidation and neuromuscular junction in M. Gastrocnemius of 24-day-old mice.

Jingyi Song, Jaap Keijer, Melissa Bekkenkamp-Grovenstein, Melanie Humphry, Claudia Carmone, Sander Grefte.

  Nicotinamide nucleotide transhydrogenase (NNT) is a key mitochondrial enzyme generating NADPH by utilizing the proton gradient produced by oxidative phosphorylation (OXPHOS), thereby linking redox homeostasis to mitochondrial energy metabolism. The commonly used C57BL/6 J mouse strain lacks functional NNT, yet its impact during early development remains unclear. This study aimed to characterize adaptive molecular responses in the gastrocnemius muscle of young mice with NNT deficiency. Congenic Nnt deficient (NntΔ; BL6JRcc.BL6J-NntC57BL/6J/Wuhap) and wild-type (Nntwt; B6JRcc(B6J)-Nnt+/Wuhap) mouse lines were newly created. Transcriptome profiling was performed on gastrocnemius muscles of 24-day-old male mice, followed by validation of key findings. Energy metabolism emerged as the most affected process, and NntΔ mice exhibited significant reduced OXPHOS-related genes, particularly within complex I and complex V showing a downregulation of 42.2 % and 50 % of their subunits, respectively. Additionally, expression of Cpt1b, Cpt2, and Slc25a20, involved in fatty acid transport, was reduced by 33 %, 19 % and 23 %, respectively. These results may explain the trend toward decreased oxygen consumption rates using palmitoylcarnitine (29 %; P-value = 0.068) and octanoylcarnitine (18 %; P-value = 0.081). CHRNA1, a protein critical for neuromuscular junction (NMJ) function, was also downregulated by 31 %. These results suggest that functional loss of NNT impairs mitochondrial energy pathways and β-oxidation, potentially influencing NMJ in the gastrocnemius muscle during development.

Keywords:  Mitochondria; NNT; OXPHOS

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148609
Int J Mol Sci. 2025 Oct 11. pii: 9900. [Epub ahead of print]26(20):

microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.

Simone Tomasini, Emanuele Monteleone, Anna Altieri, Francesco Margiotta, Fereshteh Dardmeh, Hiva Alipour, Anja Holm, Sakari Kauppinen, Riccardo Panella.

  MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity-enhancing oxidative metabolism-and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health.

Keywords:  ASO; DMD; antimiRs; autophagy; fibrosis; miR-22; miRNA therapeutics; microRNA; muscle atrophy; oxidative metabolism

DOI:  https://doi.org/10.3390/ijms26209900
Int J Mol Sci. 2025 Oct 18. pii: 10145. [Epub ahead of print]26(20):

Molecular Framework of the Onset and Progression of Skeletal Muscle Aging.

Thomas Horlem, Stephanie Rubianne Silva Carvalhal, Sandro José Ribeiro Bonatto, Luiz Cláudio Fernandes.

  Aging is a multifactorial process that progressively disrupts cellular and tissue homeostasis, affecting all organ systems at distinct rates and predisposing individuals to chronic diseases such as cancer, type II diabetes, and sarcopenia. Among these systems, skeletal muscle plays a central role in healthspan decline, yet the precise onset of its deterioration remains unclear. Most studies emphasize late-life models, overlooking the transitional phase of middle age, when initial alterations emerge. Evidence indicates that middle-aged muscle exhibits aberrant metabolism, impaired insulin sensitivity, and an early, gradual reduction in mass, suggesting that decline begins long before overt sarcopenia. This narrative review synthesizes current findings on linear and non-linear molecular biomarkers associated with the onset of skeletal muscle aging, aiming to improve early detection of muscular alterations and support the development of interventions that delay or prevent functional decline.

Keywords:  aging; metabolism; middle age; narrative review; skeletal muscle

DOI:  https://doi.org/10.3390/ijms262010145
Biol Trace Elem Res. 2025 Oct 31.

Arsenic Exposure Alters Liver Metabolism and Accelerates Skeletal Muscle Atrophy in Female BALB/c Mice.

Deogade Sakshi Rajeshwar, Sree Vaishnavi Nalla, Itishree Dubey, Rohit Kumar Gautam, Shivani Bhardwaj, Richa Shrivastava, Sapana Kushwaha.

  The liver and skeletal muscle are metabolically interconnected organs vital for maintaining systemic homeostasis. Arsenic toxicity is known to adversely affect both organs individually, yet the mechanistic link between arsenic-induced liver dysfunction and skeletal muscle deterioration remains unclear. This study aimed to investigate whether arsenic-induced alterations in hepatic metabolism are associated with changes in skeletal muscle health. BALB/c mice were divided into four groups: Control, 0.2 ppm arsenic, 2 ppm arsenic, and 20 ppm arsenic. For 30 days, sodium arsenite was administered in the drinking water ad libitum. Arsenic exposure led to elevated serum ALT and AST levels, increased hepatic lipid accumulation, and dysregulated the expression of oxidative stress defense components (Nrf2/Keap1), lipid metabolism regulators (PPAR-γ and PPAR-α), β-oxidation and lipogenic enzymes (CPT-1, and SREBP-1), as well as hepatic energy sensors (p-mTOR and p-AMPK). These hepatic changes were accompanied by oxidative stress and elevated proinflammatory cytokines (TNF-α, IL-6) in the liver and serum. Concurrently, skeletal muscle exhibited functional decline, as evidenced by decreased grip strength and elevated serum creatine kinase levels. Histological and Succinate dehydrogenase (SDH) analysis further revealed atrophy, characterized by reduced fiber cross-sectional area and a fiber-type shift from fast-twitch (Type II) to slow-twitch (Type I) fibers respectively. At the molecular level, arsenic exposure upregulated the muscle-specific ubiquitin ligases MuRF1 and atrogin-1, accompanied by NF-κB activation, indicating increased proteolysis and inflammation. Additionally, decreased irisin expression in both liver and muscle and reduced serum insulin levels indicated systemic metabolic dysregulation. Correlation analysis of inflammatory markers with indices of liver and muscle injury, together with evidence of crosstalk between these tissues, revealed significant associations. Collectively, these findings suggest that arsenic-induced hepatic disturbances may indirectly contribute to skeletal muscle wasting via systemic inflammation, supporting the possible involvement of a liver-muscle axis in arsenic toxicity.

Keywords:  Arsenic; Inflammation; Lipid metabolism; Liver; Skeletal muscle

DOI:  https://doi.org/10.1007/s12011-025-04839-z
Cells. 2025 Oct 12. pii: 1586. [Epub ahead of print]14(20):

Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions.

Alexander Kalinkovich, Gregory Livshits.

  Skeletal muscle pathologies, including sarcopenia, inflammatory myopathies, and various muscular dystrophies, are strongly influenced by chronic low-grade inflammation and impaired proteostasis. Immunoproteasomes (IMPs), inducible proteolytic complexes activated by pro-inflammatory cytokines, are emerging as regulators linking immune signaling to protein quality control. Evidence suggests that IMPs have paradoxical, context-dependent roles in skeletal muscle. On one hand, they can support proteostasis and muscle regeneration under stress; on the other, persistent activation may sustain cytokine production, antigen presentation, and maladaptive immune-muscle interactions, promoting chronic inflammation and muscle wasting. Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. Yet, their use in skeletal muscle pathologies is controversial; while inhibition may dampen harmful immune activation, it could also impair muscle repair and proteostasis. This review summarizes current findings, highlights key contradictions, and explores unresolved questions about the role of IMPs in skeletal muscle pathologies. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context.

Keywords:  chronic inflammation; immunoproteasomes; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/cells14201586
Int Immunopharmacol. 2025 Oct 30. pii: S1567-5769(25)01711-4. [Epub ahead of print]167 115723

Urolithin A promotes peripheral nerve regeneration via TFEB-mediated mitophagy and NLRP3 inflammasome suppression.

Zhe Zhang, Shanying Xiao, Dongbu Tian, Tao Lin, Kongmei Luo, Dong Peng, Yixin Bo, Anhao Guo, Yujie Hu, Long Wu, Hede Yan.

   BACKGROUND: Peripheral nerve injury (PNI) often results in incomplete recovery due to persistent neuroinflammation and mitochondrial dysfunction. Here, we investigated the therapeutic potential of Urolithin A (UA), a gut microbiota-derived metabolite, in promoting nerve regeneration by modulating mitophagy and inflammasome activation.
OBJECTIVE: To evaluate whether UA enhances peripheral nerve regeneration by activating TFEB-mediated mitophagy and inhibiting NLRP3 inflammasome activation.
METHODS: In a rat sciatic nerve crush injury model and Schwann cell cultures, UA effects were evaluated using behavioral tests, histological analysis, transmission electron microscopy, immunofluorescence, Western blotting, and molecular docking.
RESULTS: UA administration significantly improved sciatic functional index, reduced muscle atrophy, and enhanced axonal regeneration and remyelination. Mechanistically, UA promoted transcription factor EB (TFEB) nuclear translocation, upregulated autophagy-lysosomal genes, and facilitated clearance of damaged mitochondria, leading to reduced ROS levels and suppression of NLRP3 inflammasome activation. These effects were abolished by TFEB knockdown or autophagy inhibition, indicating a TFEB-dependent mechanism. Molecular docking suggested direct binding between UA and TFEB.
CONCLUSION: UA facilitates peripheral nerve repair by coupling TFEB-mediated mitophagy with NLRP3 inflammasome inhibition. This dual action provides a promising non-invasive therapeutic strategy for PNI and warrants further translational research.

Keywords:  Mitophagy; NLRP3 inflammasome; Peripheral nerve regeneration; Urolithin A

DOI:  https://doi.org/10.1016/j.intimp.2025.115723
In Vivo. 2025 Nov-Dec;39(6):39(6): 3406-3411

Impact of the Timing of Initial Anamorelin Administration in Advanced Gastrointestinal Cancer With Cancer Cachexia.

Daisuke Yoshida, Makoto Ishimatsu, Shuto Nakashima, Kouji Nakano, Shunsuke Ishida, Hiroki Orimoto, Tsukasa Miyagahara, Kazuhiro Yada, Toshifumi Matsumoto, Hirofumi Kawanaka.

   BACKGROUND/AIM: Cachexia is a multifactorial syndrome that adversely affects the prognosis of patients with gastrointestinal cancer. Although anamorelin has been shown to improve appetite and body weight, the optimal timing of its initiation remains unclear. This study evaluated the effects of the timing of anamorelin initiation on nutritional recovery and clinical outcomes in patients with gastrointestinal cancer cachexia.
PATIENTS AND METHODS: We retrospectively reviewed 42 patients with gastric (n=17) or colorectal cancer (n=25) complicated by cachexia who received 100 mg of anamorelin once daily between August 2021 and December 2024. Changes in body weight, food intake, and nutritional status were assessed before and after anamorelin administration, and overall survival was analyzed according to the type of cancer.
RESULTS: Initially, patients had experienced a mean body weight loss of 15.9±1.7% relative to the pre-diagnosis baseline. After four weeks, mean body weight increased by 2.9% (p<0.001), food intake improved significantly from 30.5%±0.3% to 57.1%±0.5% (p<0.001), and the Patient-Generated Subjective Global Assessment short form (PG-SGA SF) score decreased from 12.3±0.4 to 10.3±0.9 (p=0.003). The median overall survival was 17.9 months for gastric cancer and 36.8 months for colorectal cancer, with no significant difference between the two groups (p=0.089).
CONCLUSION: Anamorelin improved body weight, food intake, and nutritional status in patients with advanced gastrointestinal cancer cachexia. However, the modest degree of recovery suggests that earlier administration, before substantial weight and muscle loss, may maximize therapeutic benefits, support treatment continuity, and potentially improve survival outcomes. Therefore, early intervention should be considered in the clinical management of cancer cachexia.

Keywords:  Anamorelin; cancer cachexia; gastrointestinal cancer

DOI:  https://doi.org/10.21873/invivo.14137