bims-musmir 2025-08-31 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–08–31
27 papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Klotho Deficiency Promotes Skeletal Muscle Weakness and Is Associated with Impaired Motor Unit Connectivity.
Mutual reinforcement of lymphotoxin-driven myositis and impaired autophagy in murine muscle.
PRMT1 (protein arginine methyltransferase 1) is essential for neuromuscular junction and mitochondrial homeostasis via mitophagy regulation.
Mitochondrial Dysfunction Contributes to Sustained Muscle Loss After Cardiac Surgery: A Prospective Observational Study.
Multiple organs exhibit exacerbated cachexia in male mice with colon cancer than females.
Strength training while dehydrated causes excessive oxidative stress in skeletal muscle.
Physical Activity, Exerkines, and Their Role in Cancer Cachexia.
NAD+ dyshomeostasis in RYR1-related myopathies.
RNA Sequencing on Muscle Biopsies from Exertional Rhabdomyolysis Patients Revealed Down-Regulation of Mitochondrial Function and Enhancement of Extracellular Matrix Composition.
Cancer Cachexia Rehabilitation in a Novel Outpatient Clinical Program.
Muscle Aging Heterogeneity: Genetic and Structural Basis of Sarcopenia Resistance.
Downregulation of the mitochondrial tRNA-derived fragment mt-tRF-LeuTAA enhances skeletal muscle insulin sensitivity.
Ageing-Dependent Thyroid Hormone Receptor α Reduction Activates IP3R1-Meditated Ca2+ Transfer in MAM and Exacerbates Skeletal Muscle Atrophy in Mice.
Reduced Muscle Loss in Patients With NSCLC Taking Fibrates: Findings From a Retrospective Observational Study.
An Elongator mouse model of ALS spotlights TDP-43 in the motor neuron nucleolus.
Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.
Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength.
Downregulation of microRNA-494 drives mitochondrial biogenesis and function in trained muscle.
Reversible oxidative modifications partially cause myofibrillar active and passive force decline in early phase of immobilization.
Prehabilitation for muscle wasting in cancer: do definitions matter?
Convergent skeletal muscle cytokine responses to TFEB overexpression and voluntary wheel running reflect sex-based variability to exercise adaptations in mice.
Activation of polo-like kinase 1 correlates with selective motor neuron vulnerability in familial ALS.
Unlocking new mechanisms for future ALS therapies: early interventions with cholinergic antagonists reduce neuromuscular decline.
Semaglutide use is associated with neuromuscular junction degradation in older adults with type II diabetes mellitus.
Uncoupling protein 3 (UCP3) regulates energy and stress related pathways in undifferentiated skeletal muscle myoblasts.
Ruxolitinib alleviated muscle atrophy in cancer cachexia by inhibiting IL-6/JAK/STAT3 signaling pathway in mice.
Atractylenolide III Mitigates Alzheimer's Disease by Enhancing Autophagy via the YY1-TFEB Pathway.

Int J Mol Sci. 2025 Aug 19. pii: 7986. [Epub ahead of print]26(16):

Klotho Deficiency Promotes Skeletal Muscle Weakness and Is Associated with Impaired Motor Unit Connectivity.

Linda A Bean, Connor Thomas, Juan F Villa, Alexander J Fitt, Areli Jannes S Javier, Akanksha Agrawal, Hanna Whitney, Guilherme Nascimento Dos Santos, Kenneth E White, Joshua R Huot, Steven S Welc.

  Muscle wasting and weakness are critical clinical problems that limit mobility and independence, reduce health span, and increase the risk of physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho-null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic GPDH enzymatic activity also increased. Klotho-deficient mice showed impaired muscle contractility, with reduced twitch force, torque, and contraction-relaxation rates. RNA sequencing revealed upregulation of synaptic and fetal sarcomeric genes, prompting us to examine muscle innervation. Klotho deficiency led to neuromuscular junction remodeling, myofiber denervation, and functional motor unit loss. Loss of motor units correlated with absolute torque. Collectively, these findings reveal a novel mechanism through which systemic Klotho deficiency disrupts muscle synapses and motor unit connectivity, potentially contributing to muscle wasting and weakness.

Keywords:  Klotho; motor unit; skeletal muscle; wasting

DOI:  https://doi.org/10.3390/ijms26167986
Brain. 2025 Aug 25. pii: awaf260. [Epub ahead of print]

Mutual reinforcement of lymphotoxin-driven myositis and impaired autophagy in murine muscle.

Juliane Bremer, Judith Nagel, Jana Zschüntzsch, Kamil K Zajt, Tayfun Palaz, Thomas Blank, Aylin Ikis, Laura A Fischer, Anna S M Sensmeyer, Lara Wiechers, Josef J Reichelt, Kai P Hofmann, Monika J Wolf, Corinna Leuchtenberger, Priyanka Tripathi, Claudia Einer, Hans Zischka, Ulrike Rothermel, Anna-L Eck, Regina Reimann, Veronika Kana, Elisabeth Rushing, Adriano Aguzzi, Marco Prinz, David Liebetanz, Francesca Odoardi, Chao-Chung Kuo, Joachim Weis, Florian Kraft, Jens Schmidt, Mathias Heikenwälder.

  Inclusion body myositis (IBM) is a progressive muscle disorder characterized by inflammation and degeneration with altered proteostasis. To better understand the interrelationship between these two features, we aimed at establishing a novel preclinical mouse model. First, we used quantitative PCR to determine expression of pro-inflammatory chemo- and cytokines including lymphotoxin (LT)-signaling pathway components in human skeletal muscle tissue diagnosed with myositis. Based on these results we generated a mouse model that we analyzed at the histological, ultrastructural, transcriptional, biochemical, and behavioral level. Lastly, we subjected this model to anti-inflammatory treatments. After confirming and extending previous data on activation of lymphotoxin (LT)-signaling in human myositis, we generated distinct transgenic mouse lines co-expressing LTα and -β in skeletal muscle fibers. Transgenic mice displayed chronic myositis accompanied by dysregulated proteostasis, including an altered autophagolysosomal pathway that initially shows signs of activation and later exhaustion and decreased flux. To enhance the latter, we genetically impaired autophagy in skeletal muscle cells. Autophagy impairment alone induced a pro-inflammatory transcriptional state, but no obvious cellular inflammation. However, the combination of LT-driven myositis with autophagy impairment induced the full spectrum of characteristic molecular and pathological features of IBM in skeletal muscle, including protein inclusions with typical ultrastructural morphology and mild mitochondrial pathology. Our attempts to treat the pathology by subjecting these mice to corticosteroids or anti-Thy1.2 antibodies mirrored recent treatment failures in humans, i.e., none of these treatments resulted in significant clinical improvement of motor performance or the transcriptional profile of muscle pathology. In summary, these data provide evidence that inflammation and autophagy disruption play a synergistic role in the development of IBM-like muscular pathology. Furthermore, once established, IBM-like pathology in these mice, as in human IBM patients cannot be reverted or prevented from progression by conventional means of immunosuppression. We expect that this novel mouse model will help to identify future treatment modalities for IBM.

Keywords:  NF-κB signaling; autophagy; inclusion body myositis; lymphotoxin; lymphotoxin signaling; myositis

DOI:  https://doi.org/10.1093/brain/awaf260
Autophagy. 2025 Sep 01. 1-18

PRMT1 (protein arginine methyltransferase 1) is essential for neuromuscular junction and mitochondrial homeostasis via mitophagy regulation.

Ju-Hyeon Bae, Chang-Lim You, Yideul Jeong, June Kim, Jinwoo Lee, Hyeon-Ju Jeong, Hyebeen Kim, Tuan Anh Vuong, Youngdae Gwon, Gyu-Un Bae, Jong-Sun Kang.

  The neuromuscular junction (NMJ) is essential for transmitting neural stimulus to muscles, triggering muscle contraction. Mitochondria are enriched in NMJ to support the energy needs required for neuromuscular function and stability. Thus, maintaining mitochondrial homeostasis through the clearance of damaged mitochondria, a process known as mitophagy, is vital for preserving neuromuscular health. Here, we highlight the crucial role of muscle PRMT1 in maintaining NMJ and mitochondrial homeostasis via mitophagy regulation. PRMT1 is distinctively expressed in myofibers, accumulating in the postsynaptic area, with its levels upregulated in denervated muscles. PRMT1-ablated muscles displayed disrupted NMJs and an accumulation of abnormal mitochondria, accompanied by increased mitochondrial oxidative stress. Additionally, prmt1 depletion in muscles specifically impaired TBK1 (TANK binding kinase 1)-OPTN (optineurin)-mediated mitophagy. Overall, our findings suggest that PRMT1 plays a critical role in maintaining NMJ and mitochondrial health by regulating selective mitophagy through TBK1-OPTN.Abbreviations: ADMA: asymmetric arginine dimethylation; BTX: α-bungarotoxin; EDL: extensor digitorum longus; FDB: flexor digitorum brevis; GAS: gastrocnemius; NMJ: Neuromuscular junction; Mko: mice with muscle-specific prmt1 ablation; MTOR: mechanistic target of rapamycin kinase; OPTN: optineurin; PRMT1: protein arginine methyltransferase 1; SA: sodium arsenate; SNI: sciatic nerve crush injury; Sol: soleus; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; TOMM20: translocase of outer mitochondrial membrane 20; TA: tibialis anterior; VDAC1: voltage dependent anion channel 1.

Keywords:  Mitophagy; PRMT1; TBK1; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2025.2551477
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70051

Mitochondrial Dysfunction Contributes to Sustained Muscle Loss After Cardiac Surgery: A Prospective Observational Study.

Ashley N Thomas, Antonis Kalakoutas, Martin Yates, John Yap, Julie Sanders, Paul Kemp, Mark J D Griffiths.

   BACKGROUND: As a major systemic insult, cardiac surgery can lead to significant muscle loss, which increases the time to recovery as well as being correlated with mortality. Highly variable loss of muscle mass (0%-40% rectus femoris cross-sectional area [RFcsa]) and strength in the week after surgery has aided understanding of mechanisms of sarcopenia after acute illness. To include muscle recovery, patients' muscle phenotype beyond the first week after surgery and up to their return as outpatients was studied and correlated with protein and metabolomic markers.
METHODS: Patients undergoing elective aortic valve surgery were recruited. Muscle mass (RFcsa), strength (handgrip, knee extension and spirometry), body composition (by bioimpedance) and health-related quality of life (generic questionnaire EQ-5D-5L) were determined pre-operatively, 7 days after surgery and at outpatient follow-up. Blood samples were taken on Days 0, 1, 3, 7 and follow-up. The plasma metabolome was determined in 20 patients at Days 0, 3, 7 and follow-up.
RESULTS: Of 31 participants, 20 were male: mean age 68.8 years with a range between 48 and 85 years. Proportionate mean loss of RFcsa between pre-op and Day 7 values was 6.44% [95% CI 4.21 to 8.68, n = 31]; between pre-op and follow-up 9.69% [95% CI 4.92 to 14.96, n = 22]; and between Day 7 and follow-up 3.60% [95% CI -1.30 to 8.48, n = 22]. By contrast to measures of muscle bulk, the strength and functionality assessments (knee extension, handgrip, spirometry and short physical performance battery) decreased in the first week after surgery (pre-op to Day 7) followed by a return to baseline (Day 7 to follow-up). Health-related quality of life (cross-walk index) changed little over the course of the study but correlated positively at follow-up with muscle bulk (RFcsa: r = 0.58 [95% CI 0.19 to 0.81] p = 0.005) and strength of knee extension (r = 0.54 [95% CI 0.14 to 0.79] p = 0.010) and handgrip (r = 0.63 [95% CI 0.27 to 0.83] p = 0.002: n = 22). Both pre-operative and peak (Day 3) plasma levels of short-chain acyl-carnitine markers of mitochondrial dysfunction correlated with proportional muscle loss at follow-up and with strength at all timepoints.
CONCLUSIONS: Prolonged follow-up after aortic surgery demonstrated a divergence between the consistent recovery of strength and a significant proportion of patients continuing to lose muscle bulk. Markers of baseline and acute mitochondrial dysfunction predicted poor muscle outcomes up to outpatient follow-up.

Keywords:  aortic surgical procedures; critical illness myopathy; metabolomics; mitochondria; muscle regeneration; muscle strength recovery; muscular atrophy; pathology

DOI:  https://doi.org/10.1002/jcsm.70051
J Adv Res. 2025 Aug 18. pii: S2090-1232(25)00643-5. [Epub ahead of print]

Multiple organs exhibit exacerbated cachexia in male mice with colon cancer than females.

Mara Barone, Martina Lunardi, Andrea David Re Cecconi, Federica Palo, Davide Olivari, Fulvia Cerruti, Paolo Cascio, Lorenzo Castagnoli, Martina Bigliardi, Laura Pasetto, Valentina Bonetto, Mariarita Galbiati, Angelo Poletti, Rosanna Piccirillo.

   INTRODUCTION: Cachexia is a lethal syndrome with massive muscle wasting that occurs in 60% of colon cancer patients. Several studies in humans and mice show that males are more prone than females to muscle atrophy caused by colorectal cancer. Understanding whether muscle atrophy precedes or follows other organ alterations may unravel the sex-specific drivers of cachexia.
OBJECTIVES: In two mouse models of colon cancer, we explored when cachexia affects multiple organs in both sexes and their sex development, if/how sex hormone may affect in vitro the inflammatory state of colon adenocarcinoma C26, HCT116 and human primary colorectal cancer cells and in vivo the progression of cachexia in C26-carriers.
METHODS: We compared tumor growth and cachexia-related responses in C26 males and females and C57BL/6J-ApcMin/+ mice of both sexes. C26, HCT116 and human primary colorectal cancer cells exposed to 17β-estradiol or the antagonist fulvestrant were analysed for Il-6 expression and secretion. β-estradiol 3-benzoate was given to C26 males.
RESULTS: In both models, cancer-bearing males display more/earlier muscle wasting than females. Muscle proteasome activity is enhanced only in cachectic males and only when they were sexually mature. During cachexia hypogonadism appears earlier in males than females of both models. Tumor-bearing females as long as they are "cycling" are more preserved from cachexia than males. Circulating levels of IL-6 increased more in C26 males than C26 females and spleens were bigger in C26 males also displaying more atrophic and inflamed muscles. 17β-estradiol halved the expression of Il-6 and abrogated the secretion of IL-6 from C26 cells, while fulvestrant surprisingly highly enhanced Il-6 expression, supporting an anti-inflammatory effect of estrogens directly on C26 cells. Similar data were obtained from human (primary) colorectal cancer cells. In vivo β-estradiol 3-benzoate prevented some signs of cachexia in C26 carriers.
CONCLUSION: Overall, we herein report a novel direct role of 17β-estradiol on colon cancer cells explaining why multiple tissues from males display more signs of cachexia than females.

Keywords:  Cancer cachexia; Colon cancer; Mouse models; Sex difference; Sex hormones

DOI:  https://doi.org/10.1016/j.jare.2025.08.028
J Physiol. 2025 Aug 22.

Strength training while dehydrated causes excessive oxidative stress in skeletal muscle.

Geneviève J DesOrmeaux, Jeremias Kaiser, Logan K Townsend.



Keywords:  oxidative stress; passive dehydration; protein synthesis; resistance exercise; skeletal muscle

DOI:  https://doi.org/10.1113/JP289527
Int J Mol Sci. 2025 Aug 19. pii: 8011. [Epub ahead of print]26(16):

Physical Activity, Exerkines, and Their Role in Cancer Cachexia.

Jan Bilski, Aleksandra Szlachcic, Agata Ptak-Belowska, Tomasz Brzozowski.

  Cancer-associated cachexia is a multifaceted wasting syndrome characterized by progressive loss of skeletal muscle mass, systemic inflammation, and metabolic dysfunction and is particularly prevalent in gastrointestinal cancers. Physical activity has emerged as a promising non-pharmacological intervention capable of attenuating key drivers of cachexia. Exercise modulates inflammatory signaling (e.g., IL-6/STAT3 and TNF-α/NF-κB), enhances anabolic pathways (e.g., IGF-1/Akt/mTOR), and preserves lean body mass and functional capacity. Exercise-induced signaling molecules, known as exerkines, are key mediators of these benefits, which are released during physical activity and act in an autocrine, paracrine, and endocrine manner. However, many of these molecules also exhibit context-dependent effects. While they exert protective, anti-inflammatory, or anabolic actions when transiently elevated after exercise, the same molecules may contribute to cachexia pathogenesis when chronically secreted by tumors or in systemic disease states. The biological effects of a given factor depend on its origin, timing, concentration, and physiological milieu. This review presents recent evidence from clinical and experimental studies to elucidate how physical activity and exerkines may be harnessed to mitigate cancer cachexia, with particular emphasis on gastrointestinal malignancies and their unique metabolic challenges.

Keywords:  cancer cachexia; context-dependent signaling; exerkines; gastrointestinal cancers; metabolic dysfunction; physical activity; skeletal muscle; systemic inflammation

DOI:  https://doi.org/10.3390/ijms26168011
Skelet Muscle. 2025 Aug 22. 15(1): 22

NAD+ dyshomeostasis in RYR1-related myopathies.

Tokunbor A Lawal, Willa Riekhof, Linda Groom, Pooja Varma, Irene C Chrismer, Angela Kokkinis, Christopher Grunseich, Jessica W Witherspoon, Muslima S Razaqyar, Ninet Sinaii, Katherine G Meilleur, Lichen Xiang, Jana Buzkova, Liliya Euro, Payam Mohassel, Robert T Dirksen, Joshua J Todd.

   BACKGROUND: Pathogenic variants in RYR1 cause a spectrum of rare congenital myopathies associated with intracellular calcium dysregulation. Glutathione redox imbalance has been reported in several Ryr1 disease model systems and clinical studies. NAD+ and NADP are essential cofactors in cellular metabolism and redox homeostasis. NAD+ deficiency has been associated with skeletal muscle bioenergetic deficits in mitochondrial myopathy and sarcopenia.
METHODS: Using a new colorimetric assay and large control dataset (n = 299), we assessed redox balance (glutathione, NAD+, and NADP) in whole blood from 28 RYR1-RM affected individuals (NCT02362425). Analyses were expanded to human skeletal muscle (n = 4), primary myotube cultures (n = 5), and whole blood and skeletal muscle specimens from Ryr1 Y524S mice. The in vitro effects of nicotinamide riboside (NR) on cellular NAD+ content and mitochondrial respirometry were also tested.
RESULTS: At baseline, a majority of affected individuals exhibited systemic NAD+ deficiency (19/28 [68%] < 21 µM) and increased NADPH concentrations (22/26 [85%] > 1.6 µM). When compared to controls, decreased NAD+/NADH and NADP/NADPH ratios were observed in 9/28 and 23/26 individuals, respectively. In patient-derived myotube cultures (n = 5), NR appeared to increase cellular NAD+ concentrations in a dose and time-dependent manner at 72-h only and favorably modified maximal respiration and ATP production. Average whole blood GSH/GSSG ratio was comparable between groups, and redox imbalance was not observed in Ryr1 Y524S specimens.
CONCLUSIONS: NAD+ and NADP dyshomeostasis was identified in a subset of RYR1-RM affected individuals. Further experiments are warranted to confirm if NAD+ repletion could be an attractive therapeutic approach given the favorable outcomes reported in other neuromuscular disorders.

Keywords:   RYR1 ; Congenital myopathy; Glutathione; NAD+ ; NADP; Oxidative stress

DOI:  https://doi.org/10.1186/s13395-025-00390-6
Genes (Basel). 2025 Aug 02. pii: 930. [Epub ahead of print]16(8):

RNA Sequencing on Muscle Biopsies from Exertional Rhabdomyolysis Patients Revealed Down-Regulation of Mitochondrial Function and Enhancement of Extracellular Matrix Composition.

Mingqiang Ren, Luke P Michaelson, Ognoon Mungunsukh, Peter Bedocs, Liam Friel, Kristen Cofer, Carolyn E Dartt, Nyamkhishig Sambuughin, Francis G O'Connor.

   BACKGROUND/OBJECTIVE: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, the underlying mechanisms specific to the ER are not universally known within humans. This study aimed to evaluate whether patients with ER exhibited transcriptional signatures that were significantly different from those of healthy individuals.
METHODS: This study utilized RNA sequencing on skeletal muscle samples from 19 human patients with ER history, collected at a minimum of six months after the most recent ER event, and eight healthy controls to investigate the transcriptomic landscape of ER. To identify any alterations in biological processes between the case and control groups, functional pathway analyses were conducted.
RESULTS: Functional pathway enrichment analyses of differentially expressed genes revealed strong suppression of mitochondrial function. This suppression included the "aerobic electron transport chain" and "oxidative phosphorylation" pathways, indicating impaired energy production. Conversely, there was an upregulation of genes associated with adhesion and extracellular matrix-related pathways, indicating active restoration of muscle function in ER cases.
CONCLUSIONS: The study demonstrated that muscle tissue exhibited signs of suppressed mitochondrial function and increased extracellular matrix development. Both of these facilitate muscle recovery within several months after an ER episode.

Keywords:  RNA Sequencing; exertional rhabdomyolysis; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.3390/genes16080930
Am J Phys Med Rehabil. 2025 Jul 16.

Cancer Cachexia Rehabilitation in a Novel Outpatient Clinical Program.

Kelly Dong, Kathryn Abplanalp, Ishan Roy.

   ABSTRACT: Cancer cachexia is a tumor-induced muscle wasting syndrome that has a debilitating impact on patient functional status, quality of life, and cancer prognosis. This brief report summarizes a retrospective cohort study that aims to describe the oncological histories, functional co-impairments, therapy referral patterns, and physical therapy (PT) outcomes of 163 patients who were evaluated at a novel physiatry-led outpatient cancer cachexia clinic (2021-2023). 49% of the cohort that met Fearon consensus criteria for cachexia demonstrated increased odds of experiencing multiple impairments [OR = 7.4, p < 0.0001], specifically gluteal weakness [OR = 2.6, p = 0.0078], and 4 times the odds of receiving a walking program intervention [OR = 4.1, p = 0.0004]. PT was prescribed for 71% of the cohort, with no significant difference between cachexia and non-cachexia groups in PT order frequency [OR = 0.9, p = 0.7307] or PT initiation [OR = 0.8, p = 0.5419]. However, cachexia patients trended toward lower odds of meeting PT long-term goals or having these goals reassessed [OR = 0.2, p = 0.0032]. This study highlights cachexia prevalence, rehabilitation challenges, and the need for standardized, evidence-based treatment protocols. Gluteal weakness assessment may improve referrals to cachexia rehabilitation.

Keywords:  Cachexia Rehabilitation; Cancer Cachexia; Cancer Rehabilitation; Functional Impairment; Gluteal Weakness; Oncology; Physical Therapy

DOI:  https://doi.org/10.1097/PHM.0000000000002817
Genes (Basel). 2025 Aug 11. pii: 948. [Epub ahead of print]16(8):

Muscle Aging Heterogeneity: Genetic and Structural Basis of Sarcopenia Resistance.

Angelina Titova, Airat Bilyalov, Nikita Filatov, Stepan Perepechenov, Darya Kupriyanova, Sergei Brovkin, Dmitrii Shestakov, Natalia Bodunova, Oleg Gusev.

  Sarcopenia, the progressive loss of skeletal muscle mass and function with age, significantly contributes to frailty and mortality in older adults. Notably, muscles do not age uniformly-some retain structure and strength well into old age. This review explores the mechanisms underlying differential resistance to muscle aging, with a focus on sarcopenia-resistant muscles. We analyzed current literature across molecular biology, genetics, and physiology to identify key regulators of muscle preservation during aging. Special attention was given to muscle fiber types, mitochondrial function, neuromuscular junctions, and satellite cell activity. Muscles dominated by slow-twitch (type I) fibers-such as the soleus, diaphragm, and extraocular muscles-demonstrate enhanced resistance to sarcopenia. This resilience is linked to sustained oxidative metabolism, high mitochondrial density, robust antioxidant defenses, and preserved regenerative capacity. Key molecular pathways include mTOR, PGC-1α, and SIRT1/6, while genetic variants in ACTN3, MSTN, and FOXO3 contribute to interindividual differences. In contrast, fast-twitch muscles are more vulnerable due to lower oxidative capacity and satellite cell depletion. Unique innervation patterns and neurotrophic support further protect muscles like extraocular muscles from age-related atrophy. Resistance to sarcopenia is driven by a complex interplay of intrinsic and extrinsic factors. Understanding why specific muscles age more slowly provides insights into muscle resilience and suggests novel strategies for targeted prevention and therapy. Expanding research beyond traditionally studied muscles is essential to develop comprehensive interventions to preserve mobility and independence in aging populations.

Keywords:  muscle atrophy; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.3390/genes16080948
Am J Physiol Endocrinol Metab. 2025 Aug 26.

Downregulation of the mitochondrial tRNA-derived fragment mt-tRF-LeuTAA enhances skeletal muscle insulin sensitivity.

Chris Donnelly, Véronique Menoud, Bengt Kayser, Cécile Jacovetti, Romano Regazzi.

  The mitochondrial tRNA-derived fragment mt-tRF-LeuTAA couples mitochondrial metabolism to insulin secretion. While its role in pancreatic β-cell function is well established, its broader impact on multi-organ glucose homeostasis remains unclear. In insulin target tissues, the presence, regulation, and mechanism of action of mt-tRF-LeuTAA are entirely unexplored. This study addresses this gap by investigating the impact of diet, nutritional status and diabetes on mt-tRF-LeuTAA regulation and by assessing its role in insulin sensitivity. We examined mt-tRF-LeuTAA levels in different insulin target tissues, including skeletal muscle, liver, and epididymal white adipose tissue, of rodents under physiological and pathological conditions. In skeletal muscle myotubes, we combined subcellular fractionation, antisense oligonucleotide-mediated knockdown and glucose uptake assays to determine mt-tRF-LeuTAA's mitochondrial localization and its influence on insulin sensitivity. mt-tRF-LeuTAA levels in mouse skeletal muscle decreased twofold in response to fasting. In myotubes, this tRNA fragment was enriched in mitochondria, and its downregulation enhanced glucose uptake. While the levels of mt-tRF-LeuTAA remained unchanged in insulin target tissues of diabetic mice, we observed a skeletal muscle-specific downregulation of mt-tRF-LeuTAA in young adult rats exhibiting insulin hypersensitivity. This study identifies mt-tRF-LeuTAA as a candidate regulator of skeletal muscle insulin response. By modulating both insulin secretion and action, mt-tRF-LeuTAA appears to play a notable role in systemic metabolic control, and may represent a promising target for diabetes treatment.

Keywords:  Diabetes susceptibility; Mitochondrially-encoded tRNAs; Muscle glucose uptake; Nutritional status; mt-tRNA-derived fragments

DOI:  https://doi.org/10.1152/ajpendo.00284.2025
Cell Prolif. 2025 Aug 24. e70120

Ageing-Dependent Thyroid Hormone Receptor α Reduction Activates IP3R1-Meditated Ca2+ Transfer in MAM and Exacerbates Skeletal Muscle Atrophy in Mice.

Runqing Shi, Yusheng Zhang, Gong Chen, Jiru Zhang, Jing Liu, Hao Zhu, Minne Sun, Yu Duan.

  Sarcopenia profoundly impacts the quality of life and longevity in elderly populations. Notably, alterations in thyroid hormone (TH) levels during ageing are intricately linked to the development of sarcopenia. In skeletal muscle, the primary action of TH is mediated through the thyroid hormone receptor alpha (TRα). Emerging evidence suggests that decreased TRα expression may precipitate mitochondrial dysfunction in ageing skeletal muscle tissues. Yet, the precise mechanisms and the potential causative role of TRα deficiency in sarcopenia are not fully understood. This study suggests that TRα may regulate mitochondrial calcium (Ca2+) transport across membranes by targeting the inositol 1,4,5-trisphosphate receptor 1 (IP3R1), as evidenced by ChIP-seq and RNA-seq analyses. Experiments using naturally aged mice, skeletal muscle-specific TRα knockout (SKT) mice, and C2C12 myoblasts were conducted to investigate this process further. Findings include increased IP3R1, mitochondria-associated endoplasmic reticulum membranes (MAM), and mitochondrial Ca2+ in aged skeletal muscle. Additionally, SKT mice exhibited smaller muscle fibres, increased IP3R1 and MAM, and mitochondrial dysfunction. ChIP-qPCR and TRα manipulation in C2C12 cells showed that TRα negatively regulates IP3R1 transcription. Moreover, TRα knockdown cells exhibited increased Ca2+ transfer in MAM and mitochondrial dysfunction, which was ameliorated by the IP3R1 inhibitor 2-aminoethoxydiphenyl borate. Reintroduction of TRα improved IP3R1-mediated mitochondrial Ca2+ overload in aged cells. Our findings uncover a novel mechanism by which TRα deficiency induces mitochondrial Ca2+ overload through IP3R1-mediated Ca2+ transfer in MAM, exacerbating skeletal muscle atrophy during ageing. The TRα/IP3R1 pathway in MAM Ca2+ transfer presents a potential therapeutic target for sarcopenia.

Keywords:  IP3R1; MAM; mitochondrial Ca2+ overload; sarcopenia; senescence; thyroid hormone receptor α

DOI:  https://doi.org/10.1111/cpr.70120
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70016

Reduced Muscle Loss in Patients With NSCLC Taking Fibrates: Findings From a Retrospective Observational Study.

Rahmi Elahjji, Tahj Blow, Rahul Grover, Maurice A Hurd, Richard F Dunne, Bette J Caan, Elizabeth M Cespedes Feliciano, Andrew J Plodkowski, James H Flory, Marcus D Goncalves.

   BACKGROUND: The cancer-anorexia-cachexia syndrome (CACS) is a common and debilitating wasting disorder characterized by loss of skeletal muscle and worse morbidity and mortality. In pre-clinical studies, CACS is associated with loss of peroxisome proliferator-activated receptor alpha (PPAR-α) dependent ketone production in the liver. Fibrates are PPAR-α agonists that are commonly used to treat dyslipidemia. Treating mice with fibrates was found to prevent skeletal muscle loss. We examine whether patients with cancer treated with PPAR-α agonists experience less CACS.
METHODS: We performed a retrospective cohort study of patients (N = 6922) at Memorial Sloan Kettering Cancer Center who were diagnosed with non-small cell lung cancer (NSCLC) between 2002 and 2017 and were incidentally prescribed fenofibrate or gemfibrozil at the time of diagnosis. These patients were compared to a propensity score-matched control set who were not taking either drug. The primary outcome included a composite outcome of CACS, which included significant weight loss before or after the time of diagnosis. Secondary outcomes included change in cross-sectional skeletal muscle area over time as measured in serial CT imaging studies and overall survival. Descriptive statistics, Kaplan-Meier analysis and multivariable logistic regression were performed to compare outcomes between the two groups.
RESULTS: Among patients with NSCLC, 149 were taking fenofibrate or gemfibrozil at the time of diagnosis. A 2:1 propensity score-matched cohort of 298 patients was created that was well-matched with regard to baseline characteristics. Regarding the primary composite outcome, there was no significant difference in the prevalence of CACS between those taking fibrates and propensity-matched controls (49.7 vs. 46.6%). When skeletal muscle mass was measured directly using cross-sectional imaging, patients on fibrates were found to have lost significantly less muscle area over time (-3.3 vs.-4.2%, p = 0.03). There was no difference in overall survival between groups.
CONCLUSION: Patients with NSCLC taking fibrates at the time of diagnosis lost less muscle area over time. In a secondary analysis, this change was not associated with a change in overall survival, though this study was likely underpowered for this analysis.

Keywords:  PPAR‐α; cachexia; fibrates; lung cancer; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70016
Commun Biol. 2025 Aug 21. 8(1): 1259

An Elongator mouse model of ALS spotlights TDP-43 in the motor neuron nucleolus.

Magge Snow, BreAnna Cameron, Renzie Pond, Rachel Trudell, Sara Snyder, Lauryn Torres-Hernandez, Devyn Deschamps, Danara Tulimaiau, Kiana Hawkinson, Morgan Russell, Danielle Horan, Joseph Walters, James H Fox, Britni Arlian, Alain Chariot, Laurent Nguyen, Lynn George.

Dysfunction of Elongator is associated with amyotrophic lateral sclerosis (ALS). Here, we describe mouse models in which either Elongator subunit 1(Elp1) or subunit 3 (Elp3) is selectively ablated in alpha motor neurons of the spinal cord. These mice exhibit a progressive loss of motor strength and motor neuron degeneration. To interrogate the molecular mechanisms that contribute to motor neuron cell death in these mice, we examine multiple disease pathways, including the expression of TDP-43 whose cytoplasmic aggregation is associated with the human disease. Although TDP-43 is a well-characterized nuclear protein functioning in RNA metabolism and gene transcription, here we document TDP-43's robust presence in the nucleolus of wild-type motor neurons and its clearance from both the nucleus and the nucleolus of motor neurons in Elp conditional knockout mice. Thus, this study directly links dysfunction of Elongator with nucleolar disruption and TDP-43 clearing, two hallmark cellular pathologies of ALS.

DOI: https://doi.org/10.1038/s42003-025-08701-9
Nat Commun. 2025 Aug 25. 16(1): 7671

Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.

Kayleigh M Voos, Joyce Tzeng, Priya Patel, Sophie Rubinsky, Ha E Choi, Trevor Pharr, Sebastian Sookram, Joseph A Baur, Erik J Soderblom, Damaris N Lorenzo.

Mitochondrial dynamics enable cellular adaptation to fluctuations in energy demand, such as those imposed on skeletal muscle by exercise, metabolic disorders, or aging. Here, we report a novel pathway that modulates mitochondria dynamics in skeletal muscle involving the scaffolding protein ankyrin-B. Rare variants in ankyrin-B, encoded by ANK2, increase risk for cardio-metabolic syndrome in humans and mice. We show that mice selectively lacking skeletal muscle ankyrin-B have reduced endurance exercise capacity without alterations in muscle strength or systemic glucose regulation. Muscle fibers in these mice have increased oxidative stress, reduced fatty acid oxidation, and enlarged and hyperconnected mitochondria. We found that ankyrin-B interacts with and is required for efficient mitochondria recruitment of fission modulators and sarcoplasmic reticulum-mitochondria coupling. Thus, we conclude that ankyrin-B enables substrate adaptability and bioenergetic homeostasis under energetic stress, and exercise capacity by promoting efficient mitochondrial fission in skeletal muscle.

DOI: https://doi.org/10.1038/s41467-025-62977-3
Nat Aging. 2025 Aug 20.

Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength.

Peter Vrtačnik, Lara G Merino, Santhilal Subhash, Hafdís T Helgadóttir, Matthieu Bardin, Fabiana Stefani, Depin Wang, Ping Chen, Irene Franco, Gwladys Revêchon, Maria Eriksson.

Aging is associated with a progressive decline in tissue function and regenerative capacity, partly due to genomic instability, one of the hallmarks of aging1,2. Genomic instability encompasses DNA damage and the accumulation of somatic mutations in post-zygotic cells, yet the specific impact of these mutations on age-related tissue dysfunction remains poorly understood. To address this, we developed a mouse model in which genomic instability was induced specifically in muscle progenitor cells3 through targeted deletion of the Msh2 (ref. 4) and Blm5 genes. This allowed us to assess how elevated DNA damage and somatic mutations, from single-nucleotide variants (SNVs) to structural variants, affect muscle regeneration following injury. These mice exhibited impaired muscle regeneration, characterized by smaller muscle fibers, reduced muscle mass gain and decreased grip strength. Importantly, similar muscle deficits were observed in a second mouse model where somatic mutations were elevated with less substantial DNA damage. These findings provide evidence that the accumulation of somatic mutations can potentially compromise the function of somatic cells, contributing to the aging phenotype in skeletal muscle.

DOI: https://doi.org/10.1038/s43587-025-00941-y
Exp Physiol. 2025 Aug 25.

Downregulation of microRNA-494 drives mitochondrial biogenesis and function in trained muscle.

Natália Pálešová, Klára Gabrišová, Jana Babulicová, Patrik Krumpolec, Zuzana Kovaničová, Tímea Kurdiová, Salvatore Modica, Christian Wolfrum, Jozef Ukropec, Barbara Ukropcová, Miroslav Baláž.

  MicroRNAs (miRNAs) are key regulators of cellular processes, including mitochondrial function and energy metabolism. This study explores the regulation of miR-494 in skeletal muscle and circulation, investigating its response to exercise training and an acute exercise bout, its association with metabolic disorders, and the effects of electrical pulse stimulation (EPS). In addition, it validates the gene targets and physiological role of miR-494 using gain- and loss-of-function studies in primary human skeletal muscle cells. We demonstrate that miR-494 levels in both skeletal muscle and circulation are influenced by long-term exercise training, which induces adaptive changes, but remain unaffected by an acute bout of exercise. EPS does not alter miR-494 levels in cultured primary human skeletal muscle cells. Moreover, muscle miR-494 levels remain unchanged under various metabolic challenges, including obesity and type 2 diabetes. Genetic manipulation of miR-494 in primary human skeletal muscle cells modulates mitochondrial biogenesis and function, as well as lipid metabolism, through targeting PGC1A and SIRT1. Injection of a miR-494 inhibitor into skeletal muscle of mice supports the role of miR-494 in regulating Pgc1α mRNA, suggesting potential therapeutic implications. These findings highlight miR-494 as a significant modulator of mitochondrial dynamics and energy metabolism in skeletal muscle.

Keywords:  exercise; metabolism; microR‐494; mitochondria; skeletal muscle; type 2 diabetes

DOI:  https://doi.org/10.1113/EP092977
Am J Physiol Cell Physiol. 2025 Aug 26.

Reversible oxidative modifications partially cause myofibrillar active and passive force decline in early phase of immobilization.

Daiki Watanabe, Takaaki Mishima, Taku Hamada.

  Muscle immobilization leads to a decrease in muscle fiber size and contractile function, partly due to a decline in myofibrillar force. In this study, we examined the effects of reversible oxidative modifications on the decline of myofibrillar function during the early phase of immobilization. One leg of male C57BL6 mice was immobilized for 3 and 7 days, while contralateral leg was used as a non-treated (NT) control. After the given immobilization periods, mechanically skinned fibers were prepared from gastrocnemius muscle, and myofibrillar active and passive forces were assessed. Myofibrillar specific force decreased after 7 days of immobilization, although myofibrillar Ca2+ sensitivity remained unchanged. The decreased specific force was partially restored by a treatment with dithiothreitol (DTT), a reducing regent, only when applied to non-activated fibers, not activated fibers. Additionally, 3-morpholinosydnonimine (Sin-1) and peroxinitrite (ONOO-) decreased maximal force in non-activated fibers from NT but not immobilized (Im) muscles. Myofibrillar passive force decreased after 7 days of immobilization. DTT treatment increased passive force in both NT and Im fibers, with a greater improvement seen in Im fibers. Furthermore, treatment with oxidized glutathione prior to DTT treatment decreases passive force in both NT and Im fibers, with a greater reduction seen in NT fibers. These results suggest that reversible oxidative modifications partially contribute to the impairments in both myofibrillar active and passive forces, at least in the early phase of immobilization. Specifically, ONOO- and S-glutathionylation likely play an important role in active and passive force, respectively.

Keywords:  Dithiothreitol; Muscle disuse; Peroxinitrite; S-glutathionylation; Titin

DOI:  https://doi.org/10.1152/ajpcell.00554.2025
Support Care Cancer. 2025 Aug 23. 33(9): 807

Prehabilitation for muscle wasting in cancer: do definitions matter?

John Yang, Ishan Roy, Hanna Hunter.

  Frailty in older patients with cancer has been associated with functional impairments, decline in quality of life, and increased risk of mortality. There is growing interest in prehabilitation interventions designed to optimize function prior to cancer treatment to mitigate functional decline and to optimize post-treatment outcomes. This review aims to describe the heterogeneity in muscle wasting definitions, modalities used for body composition analysis, and functional outcomes investigated in exercise prehabilitation trials in cancer patients. Defining muscle loss among patients with cancer is needed to better diagnose, treat, and prevent functional decline. Utilization of a consensus on definitions for muscle wasting syndromes is critical to evaluate the efficacy of prehabilitation and exercise interventions in cancer care.

Keywords:  Cachexia; Frailty; Sarcopenia

DOI:  https://doi.org/10.1007/s00520-025-09857-0
Physiol Rep. 2025 Aug;13(16): e70519

Convergent skeletal muscle cytokine responses to TFEB overexpression and voluntary wheel running reflect sex-based variability to exercise adaptations in mice.

Dalton C Patterson, Allison Birnbaum, Ian Matthews, Constanza J Cortes.

  Running promotes skeletal muscle remodeling through metabolic and inflammatory signaling pathways, though the extent to which these responses are sex-dependent remains unclear. We profiled cytokine responses in quadriceps lysates from sedentary, voluntary wheel-running (VWR), and muscle-specific TFEB-overexpressing (cTFEB;HSACre) male and female mice. Cytokine analysis revealed 40 differentially expressed factors associated with exercise and/or TFEB overexpression, many exhibiting sex-dimorphic patterns. In males, VWR increased interleukins (IL-1α, IL-1β, IL-2, IL-5, and IL-17) and chemokines (e.g., MCP-1, CCL5, and CXCL9), including components of TNF signaling (e.g., TNFα, sTNFR1/2, and Fas ligand). These elevations were partially recapitulated by TFEB overexpression in sedentary males. In contrast, female VWR muscle showed limited changes, with significant differences restricted to IL-3, IL-3Rb, IL-13, and CXCL16. These findings demonstrate sex-specific cytokine responses to endurance-like stimuli and suggest a broader or more prolonged inflammatory remodeling profile in male skeletal muscle. Moreover, muscle-specific TFEB overexpression reproduced similar endurance-induced cytokine changes, particularly in males, highlighting TFEB as a partial molecular mimic of exercise-associated inflammatory signaling in skeletal muscle. Together, our data underscore the importance of sex as a biological variable in exercise-induced cytokine remodeling and support the utility of TFEB overexpression as a platform for prioritizing exercise-associated phenotypes.

Keywords:  cytokines; exercise; running; sex‐differences

DOI:  https://doi.org/10.14814/phy2.70519
Cell Rep. 2025 Aug 25. pii: S2211-1247(25)00884-8. [Epub ahead of print]44(9): 116113

Activation of polo-like kinase 1 correlates with selective motor neuron vulnerability in familial ALS.

Barbara Szewczyk, Vitaly Zimyanin, Julia Japtok, Aaron Held, Arun Pal, Dajana Großmann, Hannes Glaß, Alexandra V Jürs, Banaja P Dash, Maciek Bak, Marcel Naumann, Christiane Hartmann, Olena Kuksenko, René Günther, Tzu-Ting Kao, Katrin Sameith, Andreas Dahl, Jared Sterneckert, Eleonora Aronica, Neil A Shneider, Andreas Büttner, Alberto Catanese, Hemali Phatnani, Markus Kipp, Brian J Wainger, Anand Goswami, Andreas Hermann.

  Mutations in the Fused in Sarcoma (FUS) gene cause familial amyotrophic lateral sclerosis (ALS), characterized by selective degeneration of spinal motor neurons (sMNs) with relative sparing of cortical neurons (CNs). The mechanisms underlying this cell-type vulnerability remain unclear. Here, we compare CNs and sMNs derived from FUS-ALS models to assess differential responses to FUS mutations. We find that CNs are less affected than sMNs in DNA damage repair, axonal organelle trafficking, and stress granule dynamics. RNA sequencing (RNA-seq) reveals distinct transcriptomic signatures, with sMNs uniquely activating DNA damage responses involving cell cycle regulators, particularly polo-like kinase 1 (PLK1). PLK1 is highly expressed in sMNs but not CNs, correlating with greater nuclear FUS loss and splicing defects in sMNs. Cross-comparison with other familial ALS RNA-seq datasets highlights PLK1 upregulation as a shared molecular feature. These findings identify intrinsic differences between CNs and sMNs in FUS-ALS and suggest PLK1 as a potential driver of sMN vulnerability.

Keywords:  CP: Molecular biology; CP: Neuroscience; DNA damage response; FUS loss of function; FUS-ALS; PLK1; neurodegeneration; polo-like kinase 1; selective vulnerability; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116113
J Neurophysiol. 2025 Aug 27.

Unlocking new mechanisms for future ALS therapies: early interventions with cholinergic antagonists reduce neuromuscular decline.

Reynaldo Popoli, Tyler L Wells, Turgay Akay.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by motor neuron loss, leading to muscle paralysis and death. C-boutons have been shown to be part of the compensatory mechanism behind delayed symptom onset, and are most active during vigorous exercises, like swimming. When mutant mice with silenced C-boutons perform this exercise, disease progression and behavioral performance drastically improve. Genetic manipulation of C-boutons in human patients remains limited, therefore, we sought to manipulate these synapses using cholinergic antagonists in the presence and absence of exercise in a mouse model of ALS. We demonstrate that atropine and methoctramine administration yield significant improvements in human endpoints, weight maintenance, treadmill performance, and grip strength. Most remarkably, muscle innervation was greatly enhanced at humane endpoints compared to controls, suggesting these drugs provide a protective effect against loss of motor control. We found that methoctramine provided greater benefits in the absence of exercise, hinting at the presence of novel cholinergic mechanisms that can be manipulated in order to preserve motor function. Moreover, we provide evidence that these results are independent of C-boutons, and that methoctramine does not appear to cross the blood-brain barrier. Our results reveal pharmacological mechanisms by which muscle denervation can be reduced, thereby decreasing the rate of disease progression. We have uncovered a promising avenue for improving ALS symptoms by pharmacologically manipulating cholinergic transmission. This mechanism presents as a possible therapy translatable to the clinical setting, which has the potential to prevent the loss of motor control in patients with ALS.

Keywords:  Amyotrophic Lateral Sclerosis; Atropine; C-boutons; Methoctramine; Neuromuscular Junction

DOI:  https://doi.org/10.1152/jn.00306.2025
Br J Clin Pharmacol. 2025 Aug 25.

Semaglutide use is associated with neuromuscular junction degradation in older adults with type II diabetes mellitus.

Rizwan Qaisar, Imran Ullah Khan, Atif Ur Rehman, M Shahid Iqbal, Firdos Ahmad, Asima Karim.

   AIMS: Older men with type 2 diabetes mellitus (T2DM) face a heightened risk of sarcopenia. This study aimed to compare the longitudinal effects of semaglutide, a glucagon-like peptide-1 receptor agonist and sitagliptin as the control group on sarcopenia indicators and biomarkers of neuromuscular junction and neuronal health in patients with T2DM over 1 year.
METHODS: A cohort of 141 older men with T2DM (semaglutide, n = 68; sitagliptin group, n = 73) underwent assessments at baseline, 6 months and 1 year. Measured parameters included handgrip strength (HGS), gait speed, appendicular skeletal muscle mass index (ASMI), short physical performance battery (SPPB) and plasma concentrations of C-terminal agrin fragment 22 (CAF22), neurofilament light chain (NfL) and brain-derived neurotrophic factor (BDNF).
RESULTS: Over the study period, the semaglutide group exhibited significant reductions in HGS, gait speed, ASMI and SPPB scores (all P < .05). Concurrently, this group exhibited more pronounced elevation of plasma CAF22 and NfL levels compared to the sitagliptin group (all P < .05). Among the patients taking semaglutide, higher CAF22 and NfL levels generally correlated with poorer HGS, ASMI and SPPB scores. In contrast, lower BDNF levels were associated with reduced ASMI and SPPB at specific time points (all P < .05). Multiple regression analysis confirmed significant negative associations between CAF22 and NfL, and a positive association between BDNF and sarcopenia parameters, specifically among patients taking semaglutide.
CONCLUSIONS: Semaglutide treatment in older men with T2DM may be associated with a decline in muscle strength and physical performance, potentially associated with neuromuscular junction degradation and neuronal damage. These findings underscore the importance of closely monitoring musculoskeletal health in patients receiving semaglutide.

Keywords:  C‐terminal agrin fragment 22; brain‐derived neurotrophic factor; handgrip strength; neurofilament light chain; neuromuscular junction; sarcopenia; semaglutide

DOI:  https://doi.org/10.1002/bcp.70253
Am J Physiol Cell Physiol. 2025 Aug 25.

Uncoupling protein 3 (UCP3) regulates energy and stress related pathways in undifferentiated skeletal muscle myoblasts.

Austin Kindall, Yen Huynh, Jeesun Kim, Stefano Tiziani, John DiGiovanni.

  Uncoupling protein 3 (UCP3), a member of the mitochondrial solute carrier family, shares high homology with both UCP1 and UCP2. Its exact functional role has been elusive since its discovery, with previous studies primarily focusing on studying UCP3 function in differentiated skeletal muscle myotubes or whole animal models because basal levels of UCP3 protein are low in undifferentiated myoblasts. In the present study, we demonstrate that UCP3 plays a role in modulating energy and redox stress related pathways in undifferentiated muscle myoblasts. Although low, UCP3 mRNA and protein levels were detectable in WT myoblasts. Both whole-body UCP3 knockout (wKO) and conditional UCP3 knockout (cKO) myoblasts displayed increased activation of AMPK (pAMPK) and elevated levels of PPARδ/β and GLUT4 proteins compared to wild type (WT) myoblasts. This altered energy signaling was further associated with UCP3 KO myoblasts exhibiting impaired insulin-stimulated glucose uptake, while WT cells and UCP3 KO cells expressing WT UCP3 were sensitive to insulin stimulation. Moroever, UCP3 KO myoblasts had an accumulation of fatty acids and upregulation of downstream PPARδ target genes in UCP3 KO cells. Lastly, UCP3 KO myoblasts were found to be more sensitive to oxidative stress and hypoxia, due in part to a decrease in the GSH/GSSG ratio compared to WT myoblasts. Collectively, these findings demonstrate that UCP3 is a key modulator of energy sensing and oxidative stress in undifferentiated skeletal muscle myoblasts.

Keywords:  Energy signaling; Metabolism; Myoblast; Redox signaling; Uncoupling Protein 3

DOI:  https://doi.org/10.1152/ajpcell.00366.2025
J Pharm Pharmacol. 2025 Aug 20. pii: rgaf073. [Epub ahead of print]

Ruxolitinib alleviated muscle atrophy in cancer cachexia by inhibiting IL-6/JAK/STAT3 signaling pathway in mice.

Cong Li, Xiaofan Gu, Zixia Zhu, Xiaojuan Pan, Meng Fan, Xuan Liu, Xiongwen Zhang.

   OBJECTIVES: Ruxolitinib (Rux), an oral Janus tyrosine Kinase (JAK) tyrosine kinase inhibitor, has demonstrated anti-inflammatory properties and the ability to mitigate denervation-induced skeletal muscle atrophy. Here, we checked the potential efficacy of Rux on cancer cachexia and tried to clarified its mechanisms.
METHODS: The in vitro cell models of C26 or LLC CM-induced C2C12 myotubes were used to check the influence of Rux on myotube atrophy. C26 tumour-bearing mice (male BALB/c mice) were applied as the animal model to examine the effects of Rux in attenuating cachexia symptoms. Western blot analysis was utilized to investigate the potential mechanisms of Rux.
KEY FINDINGS: Rux significantly attenuated C2C12 myotube atrophy in vitro. Rux suppressed the interleukin-6 secretion by inhibiting STAT3 activation in tumour cells and macrophages. The administration of Rux prevented body weight loss and muscle wasting in C26 tumour-bearing mice without affecting tumour growth. At the end of the experiment, mice in the Rux treatment group exhibited a 6.7% increase in body weight compared to the C26 model group. Furthermore, Rux enhanced in gastrocnemius myofibres cross-sectional area and grip strength.
CONCLUSIONS: Rux ameliorates cancer cachexia muscle atrophy by inhibiting STAT3/Atrogin-1 signaling. Rux may represent a promising therapeutic candidate for the treatment of cancer cachexia.

Keywords:  IL-6/JAK/STAT3; Rux; cancer cachexia; macrophages; muscle atrophy; systemic inflammatory response

DOI:  https://doi.org/10.1093/jpp/rgaf073
Phytother Res. 2025 Aug 20.

Atractylenolide III Mitigates Alzheimer's Disease by Enhancing Autophagy via the YY1-TFEB Pathway.

Xiaowei Zhang, Shuang Chu, Yanli Huang, Zhonghua Li, Junying Song, Pan Wang, Yunfang Su, Zhenqiang Zhang, Zhishen Xie.

  Autophagy dysregulation serves as a significant pathogenic factor in Alzheimer's disease (AD), with transcription factor EB (TFEB) acting as a pivotal transcription factor that governs the process of autophagy. Atractylenolide III (AT-III), a terpenoid compound found in medicinal Atractylodes macrocephala Koidz, is well-known for its role in antioxidant and anti-inflammatory activities. The purpose of this study is to explore the beneficial impact of AT-III on AD pathology and identify the mechanisms involved. C. elegans CL4176, SH-SY5Y APPSWE, and APP/PS1 mice were used to investigate the efficacy and possible mechanism of AT-III on the treatment of AD. AT-III reduced amyloid protein (Aβ) deposition in C. elegans CL4176 heads, prolonged the paralysis time, and reduced Aβ levels in SH-SY5Y APPSWE cells. AT-III improved the learning and memory ability of APP/PS1 mice and decreased the deposition of Aβ plaques. Transcriptomics and experimental validation showed that AT-III stimulated transcription and translation of autolysosome-associated genes. AT-III enhanced co-localization of LC3 and LAMP2 with Aβ in APP/PS1 mice. Meanwhile, AT-III increased TFEB transcriptional activity, mRNA, and protein levels in the nucleus. Furthermore, AT-III enhanced the expression of Yin Yang 1 (YY1) protein, an upstream regulator of TFEB, and led to the stimulation of autophagy and lysosome biogenesis both in vivo and in vitro. The observed effects were reversed upon silencing YY1. AT-III may regulate the YY1-TFEB pathway, thereby restoring autophagy flux disturbances and ameliorating AD-related pathological changes and cognitive decline. This study provides a promising lead compound for intervention in AD.

Keywords:   C. elegans ; Alzheimer's disease; Atractylenolide III; amyloid‐β; autophagy; cognitive impairment

DOI:  https://doi.org/10.1002/ptr.70069