bims-musmir 2025-04-20 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–04–20
nineteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Human skeletal muscle mitochondrial pathways are impacted by a neuropathologic diagnosis of Alzheimer's disease.
Integrative metabolic profiling of hypothalamus and skeletal muscle in a mouse model of cancer cachexia.
Tissue-specific changes in expression of Vegfr2 in tumor and normal tissues of lymphoma-bearing BALB/c mice under chronic restraint stress.
NOR-1 Overexpression Elevates Myoglobin Expression via PERM1 and Enhances Mitochondrial Function and Endurance in Skeletal Muscles of Aged Mice.
INFLAMMATION IN CANCER CACHEXIA: STILL THE CENTRAL TENET OR JUST ANOTHER PLAYER?
Dynamic modulation of the motor neuron translatome during developmental synapse elimination.
Consecutive skeletal muscle PGC-1α overexpression: A double-edged sword for mitochondrial health in the aging brain.
Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation.
The role of microRNAs in dexamethasone-induced skeletal muscle atrophy.
Transcriptomic profiling of severe and critical COVID-19 patients reveals alterations in expression, splicing and polyadenylation.
Krüppel-like factor 5 remodels lipid metabolism in exercised skeletal muscle.
Mitochondrial and cardiovascular responses to aerobic exercise training in supine and upright positions in healthy young adults: a randomized parallel arm trial.
Housing Temperature Impacts the Systemic and Tissue-Specific Molecular Responses to Cancer in Mice.
Sarcopenic obesity is associated with long-term trajectories of physical activity and sedentary behavior.
Sarcopenia and Skeletal Muscle Loss after CAR T-cell Therapy in Diffuse Large B cell Lymphoma.
Melatonin and Exercise Restore Myogenesis and Mitochondrial Dynamics Deficits Associated With Sarcopenia in iMS-Bmal1-/- Mice.
Mitochondrial Small RNA Alterations Associated with Increased Lysosome Activity in an Alzheimer's Disease Mouse Model Uncovered by PANDORA-seq.
Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.

Neurobiol Dis. 2025 Apr 16. pii: S0969-9961(25)00132-9. [Epub ahead of print] 106916

Human skeletal muscle mitochondrial pathways are impacted by a neuropathologic diagnosis of Alzheimer's disease.

Chelsea N Johnson, Mara R Evans, Anneka E Blankenship, Casey S John, Michaella J Rekowski, Michael P Washburn, Andy Phan, Cynthia M Gouvion, Mohammad Haeri, Russell H Swerdlow, Paige C Geiger, Jill K Morris.

  Alzheimer's disease (AD) is associated with reduced lean mass and impaired skeletal muscle mitochondrial and motor function. Although primary mitochondrial defects in AD may underlie these findings, molecular alterations in AD have not been thoroughly examined in human skeletal muscle. Here, we used two human skeletal muscle types, quadriceps (n = 81) and temporalis (n = 66), to compare the proteome of individuals with a neuropathologic AD diagnosis based on AD Neuropathologic Change (ADNPC+: n = 54 temporalis, 44 quadriceps) to controls (ADNPC-: n = 27 temporalis, 22 quadriceps). We determined the effects of ADNPC status within each muscle and within apolipoprotein E4 (APOE4) carriers and APOE4 non-carriers. Pathways that support mitochondrial metabolism, including oxidative phosphorylation, were downregulated in skeletal muscle of ADNPC+ versus ADNPC- individuals. Similar mitochondrial effects were observed across muscle types and APOE4 carrier groups, but nearly four times as many proteins were altered in temporalis versus quadriceps tissue and mitochondrial effects were most pronounced in APOE4 carriers compared to APOE4 non-carriers. Of all detected oxidative phosphorylation proteins, the expression of ~29-61 % (dependent on muscle/APOE4 carrier group) significantly correlated with AD progression, ranked by Clinical Dementia Rating and ADNPC scores. Of these, 23 proteins decreased in expression with greater AD progression in all skeletal muscle type and APOE4 carrier groups. This is the first study to assess differences in the human skeletal muscle proteome in the context of AD. Our work shows that systemic mitochondrial alterations in AD extend to skeletal muscle and these effects are amplified by APOE4 and correlate with AD progression.

Keywords:  APOE4; Alzheimer's disease; Mitochondria; Proteomics; Quadriceps; Skeletal muscle; Temporalis

DOI:  https://doi.org/10.1016/j.nbd.2025.106916
Biochem Biophys Res Commun. 2025 Apr 05. pii: S0006-291X(25)00480-2. [Epub ahead of print]763 151766

Integrative metabolic profiling of hypothalamus and skeletal muscle in a mouse model of cancer cachexia.

Jae Yeon Choi, Ye Jin Kim, Jeong Seob Shin, EunBi Choi, Yuhyun Kim, Min Gwan Kim, Yang Tae Kim, Byong Seo Park, Jae Kwang Kim, Jae Geun Kim.

  Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive weight loss, muscle wasting, and systemic inflammation. Despite its clinical significance, the underlying mechanisms linking central and peripheral metabolic changes remain incompletely understood. In this study, we employed a murine model of cancer cachexia induced by intraperitoneal injection of Lewis lung carcinoma (LLC1) cells to investigate tissue-specific metabolic adaptations. Cachectic mice exhibited reduced food intake, body weight loss, impaired thermoregulation, and decreased energy expenditure. Metabolomic profiling of serum, skeletal muscle, and hypothalamus revealed distinct metabolic shifts, with increased fatty acid and ketone body utilization and altered amino acid metabolism. Notably, hypothalamic metabolite changes diverged from peripheral tissues, showing decreased neurotransmitter-related metabolites and enhanced lipid-based energy signatures. Gene expression analysis further confirmed upregulation of glycolysis- and lipid oxidation-related genes in both hypothalamus and muscle. These findings highlight coordinated yet compartmentalized metabolic remodeling in cancer cachexia and suggest that hypothalamic adaptations may play a central role in the systemic energy imbalance associated with cachexia progression.

Keywords:  Cancer cachexia; Energy metabolism; Hypothalamus; Metabolites; Muscle

DOI:  https://doi.org/10.1016/j.bbrc.2025.151766
BMC Res Notes. 2025 Apr 14. 18(1): 168

Tissue-specific changes in expression of Vegfr2 in tumor and normal tissues of lymphoma-bearing BALB/c mice under chronic restraint stress.

Alonso A Orozco-Flores, Gloria Romero-Beltrán, Diana Caballero-Hernández, Deyanira Quistián-Martínez, Ricardo Gomez-Flores, Patricia Tamez-Guerra, Cristina Rodríguez-Padilla.

   OBJECTIVE: Alteration of the expression of vascular endothelial growth factor (VEGF) and its receptors, VEGFR-1 and VEGFR-2, leads to aberrant angiogenesis in cancer; this is exacerbated by chronic stress. Our main aim was to determine the effect of chronic restraint stress on the expression of Vegfr2, the gene encoding VEGFR-2, in tumor, fat, skeletal muscle and brain in a murine model of lymphoma.
RESULTS: We found that both chronic stress and tumor burden alter Vegfr2 expression. Under chronic stress, Vegfr2 is differentially expressed in inguinal adipose tissue, decreasing in tumor-free, and increasing in tumor-bearing animals. In skeletal muscle, brain, and tumor, Vegfr2 expression was upregulated by chronic stress. Adipose tissue, brain and skeletal muscle of tumor-bearing animals also showed changes in Vegfr2 expression during tumor progression. We also found that for skeletal muscle the combination of chronic stress and tumor burden enhances Vegfr2 expression (23-folds).
CONCLUSION: Chronic stress and tumor burden influence Vegfr2 expression in normal and tumoral tissues and their co-occurrence enhances its effect on skeletal muscle.

Keywords:  Angiogenesis; Brain; Cancer; Fat; Psychogenic stress; Tumor; VEGFR-2

DOI:  https://doi.org/10.1186/s13104-025-07219-x
FASEB J. 2025 Apr 30. 39(8): e70542

NOR-1 Overexpression Elevates Myoglobin Expression via PERM1 and Enhances Mitochondrial Function and Endurance in Skeletal Muscles of Aged Mice.

Hector G Paez, Christopher R Pitzer, Peter J Ferrandi, Junaith S Mohamed, Stephen E Alway.

  Skeletal muscle health and function deteriorate with age, ultimately leading to impaired mobility and disability. Exercise is among the most effective interventions to mitigate muscle dysfunction in aging and reverse deficits. However, low attrition and an impaired capacity to exercise may limit its utility in improving muscle function in aged persons. Therefore, it is crucial to advance our mechanistic understanding of the molecular transducers of exercise to identify new and innovative drug targets to improve muscle health. Transcriptomic profiling of the human response to exercise has revealed that the nuclear receptor NR4A3 (NOR-1) is among the most responsive genes to acute exercise. Previously, we observed that in vitro knockdown of NOR-1 alters metabolic signaling in C2C12 myotubes. Specifically, we found that expression of PERM1, CKMT2, myoglobin, and mTORC1 signaling were perturbed during the knockdown of NOR-1. Herein, we extend these findings and observe that a NOR-1-PERM1-myoglobin axis regulates myoglobin expression in vitro. Furthermore, we found that aging is associated with reduced skeletal muscle NOR-1 expression. Although it is well known that exercise improves aged muscle function, whether overexpression of the exercise-responsive gene NOR-1 can confer benefits and improve muscle function in an aged context has not been evaluated. We found that the overexpression of NOR-1 in aged muscle results in enhanced muscle endurance, mitochondrial respiration, and elevated expression of NOR-1 responsive genes that we previously identified in loss of function studies. However, we also observed that overexpression of NOR-1 did not improve maximal muscle torque production and resulted in a small but significant loss of muscle wet weight that was concomitant with elevated autophagy signaling. Our data suggest that NOR-1 expression may reduce muscle fatigability and that NOR-1 drives myoglobin expression in a PERM1-dependent manner.

Keywords:  aging; autophagy; fatigue; mitochondria; muscle

DOI:  https://doi.org/10.1096/fj.202500375R
Am J Physiol Cell Physiol. 2025 Apr 18.

INFLAMMATION IN CANCER CACHEXIA: STILL THE CENTRAL TENET OR JUST ANOTHER PLAYER?

Noemi Iaia, Chiara Noviello, Maurizio Muscaritoli, Paola Costelli.

  Cancer cachexia, a multifactorial syndrome characterised by body weight loss, muscle and adipose tissue wasting, affects cancer patients. Over time, the definition of cachexia has been modified, including inflammation as one of the main causal factors. Evidences have suggested that a range of pro-inflammatory mediators may be involved in the regulation of intracellular signalling, resulting in enhanced resting energy expenditure, metabolic changes, and muscle atrophy, all of which are typical features of cachexia. Physiologically speaking, however, inflammation is a response aimed at facing potentially damaging events. Along this line, its induction in the cancer hosts could be an attempt to restore the physiological homeostasis. Interesting observations have shown that cytokines such as interleukins 4 and 6 could improve muscle wasting, supporting the view that the same mediator may exert pro- or anti-inflammatory activity depending on the immune cells involved as well as on the tissue metabolic demand. In conclusion, whether inflammation is crucial to the occurrence of cachexia or just one contributor among others, is still unclear. Indeed, inflammation could trigger cachexia, but it could also be the response to alterations of energy and protein metabolism and hormonal homeostasis. Probably both aspects are true, supporting the view that inflammation could be a crucial issue or just another player. Whether the causative role prevails over the compensatory one likely depends on the tumour type and stage, on patient lifestyle, on the presence of comorbidities, on the response to anticancer treatments, paving the way to a holistic, personalized approach to cancer cachexia.

Keywords:  Cachexia; Cancer; Cytokines; Inflammation; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00808.2024
Sci Signal. 2025 Apr 15. 18(882): eadr0176

Dynamic modulation of the motor neuron translatome during developmental synapse elimination.

Dinja van der Hoorn, Fabio Lauria, Helena Chaytow, Kiterie M E Faller, Yu-Ting Huang, Rachel A Kline, Ilaria Signoria, Kim Morris, Thomas M Wishart, Ewout J N Groen, Gabriella Viero, Thomas H Gillingwater.

The developmental sculpting of neuromuscular circuitry in early postnatal life occurs through the process of synapse elimination: Supernumerary axon inputs are gradually eliminated from the neuromuscular junction (NMJ), resulting in each muscle fiber being innervated by a single axon terminal. Here, we investigated the molecular pathways underlying this process using a ChAT-RiboTag mouse model in which we isolated ribosome-bound mRNAs in motor neurons during synapse elimination in vivo. Analysis of these mRNAs using translating ribosome affinity purification followed by RNA sequencing (TRAP-seq) revealed dynamic changes in the motor neuron translatome over the first 2 weeks of life, which were largely independent of parallel transcriptional changes and correlated with the progressive elimination of supernumerary inputs. Bioinformatic analysis identified distinct clusters of transcripts that were translated at specific time points during synapse elimination. Treating mice with two small molecules that were predicted to independently target the proteins or pathways encoded by the transcript cluster associated with neural metabolism increased the rate of synapse elimination in vivo. Together, these data provide a cell type-specific overview of temporal modifications occurring in the motor neuron translatome during synapse elimination, revealing rapid and dynamic responses to postnatal developmental cues.

DOI: https://doi.org/10.1126/scisignal.adr0176
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 12. pii: S0925-4439(25)00196-6. [Epub ahead of print]1871(6): 167851

Consecutive skeletal muscle PGC-1α overexpression: A double-edged sword for mitochondrial health in the aging brain.

Lei Zhou, Soroosh Mozaffaritabar, Erika Koltai, Smaragda Giannopoulou, Attila Kolonics, Yaodong Gu, Ricardo A Pinho, Ildiko Miklossy, Istvan Boldogh, Zsolt Radák.

  Mitochondrial dysfunction is a critical contributor to age-related functional declines in skeletal muscle and brain. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is essential for mitochondrial biogenesis and function during aging. While skeletal muscle-specific overexpression of PGC-1α is known to mimic exercise-induced benefits in young animals, its chronic systemic effects on aging tissues remain unclear. This study aimed to determine the lifelong impact of skeletal muscle-specific PGC-1α overexpression on mitochondrial health, oxidative stress, inflammation, and cognitive function in aged mice. We established three experimental groups: young wild-type mice (3-4 months old), aged wild-type mice (25-27 months old), and aged mice with skeletal muscle-specific PGC-1α overexpression (24-27 months old). In skeletal muscle, aging led to significant reductions in mitochondrial biogenesis markers, including PGC-1α, FNDC5, and mtDNA content. PGC-1α overexpression reversed this decline, elevating the expression of PGC-1α, SIRT1, LONP1, SDHA, CS, TFAM, eNOS, and mtDNA levels, suggesting preserved mitochondrial biogenesis. However, FNDC5 and SIRT3 were paradoxically suppressed, indicating potential compensatory feedback mechanisms. PGC-1α overexpression also enhanced anabolic signaling, as evidenced by increased phosphorylation of mTOR and S6, and reduced FOXO1 expression, favoring a muscle growth-promoting environment. Moreover, aging impaired mitochondrial dynamics by downregulating MFN1, MFN2, OPA1, FIS1, and PINK1. While PGC-1α overexpression did not restore fusion-related proteins, it further reduced fission-related protein and enhanced mitophagy proteins, as evidenced by increased PINK1 phosphorylation. In contrast, in the hippocampus, muscle-specific PGC-1α overexpression exacerbated age-associated mitochondrial biogenesis decline. Expression levels of key mitochondrial markers, including PGC-1α, SIRT1, CS, FNDC5, Cytochrome C, and TFAM, were further reduced compared to aged wild-type controls. mTOR phosphorylation was also significantly suppressed, whereas cognition-related proteins (BDNF, VEGF, eNOS) and performance in behavioral tests remained unchanged. Importantly, skeletal muscle-specific PGC-1α overexpression triggered pronounced oxidative stress and inflammatory responses in both skeletal muscle and the hippocampus. In skeletal muscle, elevated levels of protein carbonyls, IκB-α, NF-κB, TNF-α, SOD2, and NRF2 were observed, accompanied by a reduction in the DNA repair enzyme OGG1. Notably, similar patterns were detected in the hippocampus, including increased expression of protein carbonyls, iNOS, NF-κB, TNF-α, SOD2, GPX1, and NRF2, alongside decreased OGG1 levels. These findings suggest that the overexpression of PGC-1α in skeletal muscle may have contributed to systemic oxidative stress and inflammation. In conclusion, skeletal muscle-specific PGC-1α overexpression preserves mitochondrial biogenesis and enhances anabolic signaling in aging muscle but concurrently induces oxidative stress and inflammatory responses, which may adversely affect mitochondrial health in the brain. These results emphasize the complex role of the skeletal muscle PGC-1α during aging.

Keywords:  Aging; Hippocampus; Inflammation; Mitochondrial biogenesis; Oxidative stress; PGC-1α; Skeletal muscle

DOI:  https://doi.org/10.1016/j.bbadis.2025.167851
Int J Mol Sci. 2025 Mar 21. pii: 2867. [Epub ahead of print]26(7):

Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation.

Roberta Romano, Victoria Stefania Del Fiore, Giorgia Ruotolo, Martina Mazzoni, Jessica Rosati, Francesca Luisa Conforti, Cecilia Bucci.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Consequent to the loss of these cells, neuromuscular functions decline, causing progressive weakness, muscle wasting, and paralysis, leading to death in 2 to 5 years. More than 90% of ALS cases are sporadic, while the remaining 10% of cases are familial, due to mutations in 40 different genes. One of the most common genes to be mutated in ALS is TARDBP (transactive response DNA binding protein 43), which encodes TDP-43 (TAR DNA-binding protein 43). A mutation in exon 6 of TARDBP causes the aminoacidic substitution G376D in the C-terminal region of TDP-43, leading to its cytoplasmic mislocalization and aggregation. In fibroblasts derived from patients carrying this mutation, we found a strong increase in lysosome number, with overexpression and higher nuclear translocation of the transcription factor TFEB. In contrast, lysosomal functionality was deeply compromised. Interestingly, lysosomal activity was unaffected at an early stage of the disease, worsening in more advanced stages. Moreover, we observed the same pathological phenotype in iPSC (induced pluripotent stem cells)-derived patient motor neurons carrying the G376D mutation. Therefore, this mutation compromises the functionality of lysosomes, possibly contributing to neurodegeneration.

Keywords:  TDP-43; TFEB; amyotrophic lateral sclerosis; lysosome; neurodegeneration; neurodegenerative disease

DOI:  https://doi.org/10.3390/ijms26072867
Exp Gerontol. 2025 Apr 16. pii: S0531-5565(25)00078-6. [Epub ahead of print] 112749

The role of microRNAs in dexamethasone-induced skeletal muscle atrophy.

Subi Ren, Jie Chai, Lijuan Zhang, JiGang Li, Xi Long, Tinghuan Zhang.

  Muscle atrophy is characterized by a decrease in muscle mass, strength, and activity. Recently, it was determined that microRNAs (miRNAs) can regulate muscle atrophy and that dexamethasone (Dex), an allergy and autoimmune disorder treatment that can induce muscle atrophy. Therefore, this study was designed to identify miRNAs expressed in Dex-induced muscle atrophy in mice using small RNA sequencing. A total of 820 miRNAs were identified, with 58 miRNAs expressed explicitly in atrophic muscles. Dex-induced muscle atrophy miRNAs clustered separately from the differential miRNAs in aging, disuse, and cancer-induced muscle atrophy models. The target genes of Dex-induced muscle atrophy miRNAs were independently enriched in inositol phosphate metabolism, hypoxia-inducible factor-1 signaling pathway, etc. Of note, there was a significant increase in the volume of fat cells and adipose weight in the Dex group, suggesting that fat deposition during Dex-induced skeletal muscle atrophy is a unique and typical feature. SIMPLE SUMMARY: Dexamethasone (Dex) is a glucocorticoid used to treat allergic and autoimmune diseases, but excessive use can lead to skeletal muscle atrophy. We used dexamethasone (Dex) to build a muscle atrophy model in mice, and obvious changes had taken place in mouse body weight, muscle tissue morphology and related genes. A large number of microRNAs were found to be differentially expressed, and their functions were enriched in pathways related to muscle development. At the same time, we compared the similarities and differences of microRNAs and their functions between Dex induced muscle atrophy model and other muscle atrophy models. Finally, we were surprised to find that Dex induced muscle atrophy is specifically accompanied by the accumulation of body fat.

Keywords:  Dexamethasone; Lipid deposition; Muscle atrophy; microRNAs

DOI:  https://doi.org/10.1016/j.exger.2025.112749
Sci Rep. 2025 Apr 18. 15(1): 13469

Transcriptomic profiling of severe and critical COVID-19 patients reveals alterations in expression, splicing and polyadenylation.

Marjorie Labrecque, Elsa Brunet-Ratnasingham, Laura K Hamilton, Daniel Auld, Alexandre Montpetit, Brent Richards, Madeleine Durand, Simon Rousseau, Andrés Finzi, Daniel E Kaufmann, Martine Tetreault.

  Coronavirus disease 2019 (COVID-19) is a multi-systemic illness that became a pandemic in March 2020. Although environmental factors and comorbidities can influence disease progression, there is a lack of prognostic markers to predict the severity of COVID-19 illness. Identifying these markers is crucial for improving patient outcomes and appropriately allocating scarce resources. Here, an RNA-sequencing study was conducted on blood samples from unvaccinated, hospitalized patients divided by disease severity; 367 moderate, 173 severe, and 199 critical. Using a bioinformatics approach, we identified differentially expressed genes (DEGs), alternative splicing (AS) and alternative polyadenylation (APA) events that were severity-dependent. In the severe group, we observed a higher expression of kappa immunoglobulins compared to the moderate group. In the critical cohort, a majority of AS events were mutually exclusive exons and APA genes mostly had longer 3'UTRs. Interestingly, multiple genes associated with cytoskeleton, TUBA4A, NRGN, BSG, and CD300A, were differentially expressed, alternatively spliced and polyadenylated in the critical group. Furthermore, several inflammation-related pathways were observed predominantly in critical vs. moderate. We demonstrate that integrating multiple downstream analyses of transcriptomics, from moderate, severe, and critical patients confers a significant advantage in identifying relevant dysregulated genes and pathways.

Keywords:  Alternative polyadenylation; Alternative splicing; COVID-19; Differentially expressed genes; Pathway enrichment; Transcriptomics

DOI:  https://doi.org/10.1038/s41598-025-95905-y
Mol Metab. 2025 Apr 16. pii: S2212-8778(25)00061-4. [Epub ahead of print] 102154

Krüppel-like factor 5 remodels lipid metabolism in exercised skeletal muscle.

Konstantin Schneider-Heieck, Joaquín Pérez-Schindler, Jonas Blatter, Laura M de Smalen, Wandrille Duchemin, Stefan A Steurer, Bettina Karrer-Cardel, Danilo Ritz, Christoph Handschin.

  Regular physical activity induces a variety of health benefits, preventing and counteracting diseases caused by a sedentary lifestyle. However, the molecular underpinnings of skeletal muscle plasticity in exercise remain poorly understood. We identified a role of the Krüppel-Like Factor 5 (Klf5) in this process, in particular in the regulation of lipid homeostasis. Surprisingly, gain- and loss-of-function studies in muscle in vivo revealed seemingly opposite functions of Klf5 in the response to an acute exercise bout and chronic training, modulating lipid oxidation and synthesis, respectively. Thus, even though only transiently induced, the function of Klf5 is complex and fundamental for a normal long-term training response. These findings highlight the importance of this mediator of external stress response to adaptive remodeling of skeletal muscle tissue.

Keywords:  Klf5; exercise; lipid metabolism; skeletal muscle; stress response; transcriptional regulation

DOI:  https://doi.org/10.1016/j.molmet.2025.102154
Transl Exerc Biomed. 2025 May;2(1): 9-20

Mitochondrial and cardiovascular responses to aerobic exercise training in supine and upright positions in healthy young adults: a randomized parallel arm trial.

Nicholas Preobrazenski, Stuart P S Mladen, Ejaz Causer, Eveline Menezes, Hashim Islam, Patrick J Drouin, Michael E Tschakovsky, Brendon J Gurd.

   Objectives: Aerobic exercise training can increase skeletal muscle mitochondrial content. Supine exercise training with legs above the heart potentially augments these increases. However, the impact of supine exercise training on mitochondrial biogenesis and cardiovascular adaptations remains unclear.
Methods: In this single-centred, randomized, parallel arm trial, 19 recreationally active individuals underwent seven sessions of either supine with legs up (SUP; n=9, 6 females) or upright with legs down (UP; n=10, 7 females) aerobic training on a recumbent bike at 71 ± 7 % and 71 ± 2 % of peak work rate (WRpeak), respectively. The study aimed to test the effects of training with decreased muscle oxygenation on indices of muscle mitochondrial remodelling. Secondary outcomes included exercise performance, muscle oxygenation, and cardiovascular responses.
Results: Secondary outcomes revealed significant interaction effects for time to fatigue (TTF) and WRpeak in the SUP group during supine testing, suggesting enhanced exercise tolerance and performance. No between group interaction effects were observed for upright testing. No clear effects on mitochondrial biogenesis were observed based on expression of mitochondrial protein subunits and transcriptional regulators. Acutely, HRpeak was lower during the SUP Test compared to the UP Test. No central cardiovascular adaptations were observed following training.
Conclusions: Our exploratory analyses showed that supine aerobic training more effectively improves supine exercise tolerance and performance compared with upright training, despite no differences in measured proteins related to mitochondrial biogenesis. Further research is needed to elucidate the mechanisms underlying these postural-specific training effects.
Registration: clinicaltrials.gov: NCT04151095.

Keywords:  PGC-1α; aerobic training; cardiovascular response; exercise performance; supine exercise

DOI:  https://doi.org/10.1515/teb-2025-0002
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13781

Housing Temperature Impacts the Systemic and Tissue-Specific Molecular Responses to Cancer in Mice.

Andrea Irazoki, Emma Frank, Tang Cam Phung Pham, Jessica L Braun, Amy M Ehrlich, Mark Haid, Fabien Riols, Camilla Hartmann Friis Hansen, Anne-Sofie Rydal Jørgensen, Nicoline Resen Andersen, Laura Hidalgo-Corbacho, Roberto Meneses-Valdes, Mona Sadek Ali, Steffen Henning Raun, Johanne Louise Modvig, Samantha Gallero, Steen Larsen, Zach Gerhart-Hines, Thomas Elbenhardt Jensen, Maria Rohm, Jonas T Treebak, Val Andrew Fajardo, Lykke Sylow.

   BACKGROUND: Cancer cachexia, affecting up to 80% of patients with cancer, is characterized by muscle and fat loss with functional decline. Preclinical research seeks to uncover the molecular mechanisms underlying cachexia to identify potential targets. Housing laboratory mice at ambient temperature induces cold stress, triggering thermogenic activity and metabolic adaptations. Yet, the impact of housing temperature on preclinical cachexia remains unknown.
METHODS: Colon 26 carcinoma (C26)-bearing and PBS-inoculated (Ctrl) mice were housed at standard (ST; 20°C-22°C) or thermoneutral temperature (TN; 28°C-32°C). They were monitored for body weight, composition, food intake and systemic factors. Upon necropsy, tissues were weighed and used for evaluation of ex vivo force and respiration, or snap frozen for biochemical assays.
RESULTS: C26 mice lost 7.5% body weight (p = 0.0001 vs. Ctrls), accounted by decreased fat mass (-35%, p < 0.0001 vs. Ctrls), showing mild cachexia irrespective of housing temperature. All C26 mice exhibited reduced force (-40%, p < 0.0001 vs. Ctrls) and increased atrogene expression (3-fold, p < 0.003 vs. Ctrls). Cancer altered white adipose tissue (WAT)'s functional gene signature (49%, p < 0.05 vs. Ctrls), whereas housing temperature reduced brown adipose tissue (BAT)'s (-78%, p < 0.05 vs. ST Ctrl). Thermogenic capacity measured by Ucp1 expression decreased upon cancer in both WAT and BAT (-93% and -63%, p < 0.0044 vs. Ctrls). Cancer-driven glucose intolerance was noted at ST (26%, p = 0.0192 vs. ST Ctrl), but restored at TN (-23%, p = 0.005 vs. ST C26). Circulating FGF21, GDF-15 and IL-6 increased in all C26 mice (4-fold, p < 0.009 vs. Ctrls), with a greater effect on IL-6 at TN (76%, p = 0.0018 vs. ST C26). Tumour and WAT Il6 mRNA levels remained unchanged, while cancer induced skeletal muscle (SkM) Il6 (2-fold, p = 0.0016 vs. Ctrls) at both temperatures. BAT Il6 was only induced in C26 mice at TN (116%, p = 0.0087 vs. ST C26). At the bioenergetics level, cancer increased SkM SERCA ATPase activity at ST (4-fold, p = 0.0108 vs. ST Ctrl) but not at TN. In BAT, O2 consumption enhanced in C26 mice at ST (119%, p < 0.03 vs. ST Ctrl) but was blunted at TN (-44%, p < 0.0001 vs. ST C26). Cancer increased BAT ATP levels regardless of temperature (2-fold, p = 0.0046 vs. Ctrls), while SERCA ATPase activity remained unchanged at ST and decreased at TN (-59%, p = 0.0213 vs. TN Ctrl).
CONCLUSIONS: In mild cachexia, BAT and SkM bioenergetics are susceptible to different housing temperatures, which influences cancer-induced alterations in glucose metabolism and systemic responses.

Keywords:  bioenergetics; cancer cachexia; cold‐induced stress; thermogenic tissues; thermoneutrality

DOI:  https://doi.org/10.1002/jcsm.13781
Exp Gerontol. 2025 Apr 10. pii: S0531-5565(25)00081-6. [Epub ahead of print]204 112752

Sarcopenic obesity is associated with long-term trajectories of physical activity and sedentary behavior.

Aarón Salinas-Rodríguez, Ana Rivera-Almaraz, Betty Manrique-Espinoza.

   BACKGROUND: Sarcopenia is characterized by decreased muscle mass and strength, and when combined with obesity, it is called sarcopenic obesity (SO). Like sarcopenia, SO is associated with adverse health outcomes This study aimed to investigate the association between SO with the longitudinal, long-term trajectories of physical activity (PA) and sedentary behavior (SB).
METHODS: Data came from four waves of the WHO Study on Global AGEing and Adult Health (SAGE) in Mexico (2009, 2014, 2017, 2021). A total of 1484 older adults aged 50 years and above were included in the study. PA and SB were determined by using the Global Physical Activity Questionnaire. Sarcopenia was defined according to the criteria of the European Working Group on Sarcopenia in Older People, and obesity according to waist circumference. Growth mixture modeling was used to investigate the longitudinal trajectories of PA and SB.
RESULTS: Three longitudinal trajectories of PA and SB were found: low-PA-decreasers, moderate-PA-decreasers, and high-PA-decreasers for PA; and low-maintainers, steep-decreasers, and steep-increasers for SB. Decreased odds of SO were consistently associated with better PA and SB trajectories.
CONCLUSIONS: The results of this study showed that sustained long-term trajectories of adequate levels of PA and SB are associated with lower rates of SO. The findings of this study support the evidence that regular PA can help reduce the likelihood of developing SO.

Keywords:  Incidence; Mexico; Physical activity; Prevalence; Sarcopenic obesity; Sedentary behavior

DOI:  https://doi.org/10.1016/j.exger.2025.112752
Clin Cancer Res. 2025 Apr 16.

Sarcopenia and Skeletal Muscle Loss after CAR T-cell Therapy in Diffuse Large B cell Lymphoma.

Khushali Jhaveri, Ram Thapa, Dalia Ercan, Aditi Saha, Jerald Noble, Pranit Singh, Johannes Fahrmann, Neeraj Saini, Ranran Wu, Jennifer B Dennison, Sam Hanash, Robert R Jenq, Karnav Modi, Nicholas Figura, Julio Chavez, Bijal Shah, Taiga Nishihori, Aleksandr Lazaryan, Farhad Khimani, Christina Bachmeier, Kenneth Gage, Asmita Mishra, Fabiana Perna, Marco L Davila, Jay Spiegel, Kai Rejeski, Marion Subklewe, Frederick L Locke, Ciara Freeman, Nathan Parker, Michael D Jain.

PURPOSE: Sarcopenia is a hallmark of cancer cachexia. Chimeric antigen receptor (CAR) T-cell therapy is associated with an inflammatory state that may exacerbate sarcopenia. The relationship between CAR T-cell therapy, sarcopenia, and metabolism is poorly understood.
EXPERIMENTAL DESIGN: In 83 large B-cell lymphoma patients, the skeletal muscle index (SMI) was measured from clinical images obtained at baseline and days 30 and 90 post-therapy. Serum metabolomics (n=57 patients) was performed in the first 4 weeks.
RESULTS: Baseline sarcopenia was present in over half of patients and associated with shorter median overall survival (OS) than for non-sarcopenic patients (10.5 versus 34.3 months; P=0.006). This reduction was due to increased non-relapse mortality (NRM) with all six NRM events occurring in patients with baseline sarcopenia. In the first 30 days after CAR T-cell therapy, 1/3 of patients experienced skeletal muscle loss greater than 10%. Muscle loss was associated with higher tumor burden and neurotoxicity but was not significantly associated with long term survival. Serum metabolomics revealed an early (weeks 1-2) increase in purine metabolites, followed by a later (weeks 3-4) increase in triglyceride levels. The serum metabolite with the highest fold-increase from baseline was adipic acid, attributed to the inpatient hospital menu of Jello and other tart beverages.
CONCLUSIONS: Skeletal muscle loss after CAR T-cell therapy is common and is associated with fatty acid catabolism. Patients with baseline sarcopenia have poor tolerance and reduced survival. Future studies of dietary and exercise interventions may improve CAR T-cell therapy outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3782
J Pineal Res. 2025 Apr;77(3): e70049

Melatonin and Exercise Restore Myogenesis and Mitochondrial Dynamics Deficits Associated With Sarcopenia in iMS-Bmal1-/- Mice.

Yolanda Ramírez-Casas, José Fernández-Martínez, María Martín-Estebané, Paula Aranda-Martínez, Alba López-Rodríguez, Sergio Esquivel-Ruiz, Yang Yang, Germaine Escames, Darío Acuña-Castroviejo.

  Sarcopenia, a condition associated with aging, involves progressive loss of muscle mass, strength, and function, leading to impaired mobility, health, and increased mortality. The underlying mechanisms remain unclear, which limits the development of effective therapeutic interventions. Emerging evidence implicates chronodisruption as a key contributor to sarcopenia, emphasizing the role of Bmal1, a circadian clock gene critical for muscle integrity and mitochondrial function. In a skeletal muscle-specific and inducible Bmal1 knockout model (iMS-Bmal1-/-), we observed hallmark features of sarcopenia, including disrupted rhythms, impaired muscle function, and mitochondrial dysfunction. Exercise and melatonin treatment reversed these deficits independently of Bmal1. Building on these findings, the present study elucidates several mechanisms underlying these changes and the pathways by which melatonin and exercise exert their beneficial effects. Our findings indicate that iMS-Bmal1-/- mice exhibit reduced expression of satellite cell and muscle regulatory factors, indicating impaired muscle regeneration. While mitochondrial respiration remained unchanged, notable alterations in mitochondrial dynamics disrupted mitochondria in skeletal muscle. In addition, these mice showed alterations in muscle energy metabolism, compromised antioxidant defense, and inflammatory response. Remarkably, exercise and/or melatonin successfully mitigated these deficits, restoring muscle health in Bmal1-deficient mice. These findings position exercise and melatonin as promising therapeutic candidates for combating sarcopenia and emphasize the need to elucidate the molecular pathways underlying their protective effects.

Keywords:  Bmal1; exercise; melatonin; mitochondrial dysfunction; myogenesis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1111/jpi.70049
Int J Mol Sci. 2025 Mar 26. pii: 3019. [Epub ahead of print]26(7):

Mitochondrial Small RNA Alterations Associated with Increased Lysosome Activity in an Alzheimer's Disease Mouse Model Uncovered by PANDORA-seq.

Xudong Zhang, Junchao Shi, Pratish Thakore, Albert L Gonzales, Scott Earley, Qi Chen, Tong Zhou, Yumei Feng Earley.

  Emerging small non-coding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a previously unrecognized sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer's disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies.

Keywords:  Alzheimer’s disease; lysosome; mitochondrial; small non-coding RNAs (sncRNAs); tRNA-derived small RNAs

DOI:  https://doi.org/10.3390/ijms26073019
Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027

Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.

Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.

  Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.

Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures

DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
Cell Rep. 2025 Apr 16. pii: S2211-1247(25)00362-6. [Epub ahead of print]44(5): 115591

Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.

Mohsin Rahim, Tomasz K Bednarski, Clinton M Hasenour, Deveena R Banerjee, Irina Trenary, Jamey D Young.

  We present an isotope-based metabolic flux analysis (MFA) approach to simultaneously quantify metabolic fluxes in the liver, heart, and skeletal muscle of individual mice. The platform was scaled to examine metabolic flux adaptations in age-matched cohorts of mice exhibiting varying levels of chronic obesity. We found that severe obesity increases hepatic gluconeogenesis and citric acid cycle flux, accompanied by elevated glucose oxidation in the heart that compensates for impaired fatty acid oxidation. In contrast, skeletal muscle fluxes exhibit an overall reduction in substrate oxidation. These findings demonstrate the dichotomy in fuel utilization between cardiac and skeletal muscle during worsening metabolic disease and demonstrate the divergent effects of obesity on metabolic fluxes in different organs. This multi-tissue MFA technology can be extended to address important questions about in vivo regulation of metabolism and its dysregulation in disease, which cannot be fully answered through studies of single organs or isolated cells/tissues.

Keywords:  CP: Metabolism; cardiac metabolism; fluxomics; isotope labeling; liver metabolism; metabolic flux analysis; metabolomics; muscle metabolism; obesity; steatotic liver disease; systems biology

DOI:  https://doi.org/10.1016/j.celrep.2025.115591