Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with goal extending healthspan. However, frequent dosing disrupts metabolic health during sedentary conditions and abates anabolic response to exercise. Intermittent once weekly minimizes many negative side effects in mice. it remains unknown how different schedules impact metabolic, physical, skeletal muscle adaptations voluntary exercise training. Therefore, we tested hypothesis that intermittent (2mg/kg; 1x/week) would avoid detrimental on 8 weeks progressive weighted wheel running (PoWeR) adult female mice (5-month-old) by evading sustained inhibitory signaling more 3x/week). Frequent but not suppressed mTORC1 PoWeR trained improved maximal capacity, absolute grip strength, myofiber hypertrophy no differences between vehicle or treated Conversely, had impaired glucose tolerance insulin sensitivity compared after PoWeR; however, reduced intolerance versus rapamycin. Collectively, these data suggest 1) is largely compatible physical benefits 2) body composition metabolism context may be dosing.

Language: Английский

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Cooperation of a polymerizing SAM domain and an intrinsically disordered region enables full SAMD1 function on chromatin

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(6)

Published: March 20, 2025

Abstract Transcription factors orchestrate gene expression through a myriad of complex mechanisms, encompassing collaborations with other transcription and the formation multimeric complexes. The chromatin-binding protein SAMD1 [sterile alpha motif (SAM) domain-containing 1] binds to unmethylated CpG-rich DNA utilizing its N-terminal winged-helix (WH) domain. Additionally, C-terminal SAM domain, which mediates interactions itself L3MBTL3, is crucial for chromatin binding. precise role domain in this process remains unclear. Using structural analyses, we elucidated distinct homopolymerization modes within domains L3MBTL3 SAMD1, alongside their heterodimerization architecture. Interestingly, necessitates not only WH but also proline/alanine-rich intrinsically disordered region (IDR) efficient IDR essential ability form large polymers, functionality determined by integrity rather than specific sequence. Mutagenesis studies underscore critical arginines polymerization, binding, biological function SAMD1. These findings propose model structured unstructured regions cooperate coordinated fashion facilitate This work provides new insights into diverse mechanisms employ interact regulate expression.

Language: Английский

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Myocellular adaptations to short‐term weighted wheel‐running exercise are largely conserved during C26‐tumour induction in male and female mice

Experimental Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 24, 2025

Abstract This study investigated whether performing a translatable murine model of concurrent training after tumour induction affects adaptations in juvenile male and female tumour‐bearing mice. Male Balb/c mice were injected bilaterally with colon‐26 adenocarcinoma (C26) cells or PBS at 8 weeks age. Half the then performed 24 days voluntary wheel running progressively increased load (PoWeR training), whereas rest remained sedentary. Deuterium oxide‐based protein synthesis, muscle fibre‐type composition size, turnover mitochondrial markers assessed 25 induction. Average gastrocnemius fibre size was smaller PoWeR regardless males females, concomitant pronounced faster‐to‐slower transition. In mice, resulted greater Redd1 , Murf1 Pgc1α mRNA content than all other groups, along lower overall volume, food consumption synthesis relative to control animals. Molecular measures followed similar pattern PoWeR, but consumption, volume maintained. lowered gonadal fat during cancer cachexia both sexes, heart weight observed presence. A negative correlation found between distance. Collectively, has effect on cellular phenotype sexes presence, present despite molecular dysregulation.

Language: Английский

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Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival

The FASEB Journal, Journal Year: 2022, Volume and Issue: 37(1)

Published: Dec. 21, 2022

Cancer survivors suffer impairments in skeletal muscle terms of reduced mass and function. Interestingly, human possesses an epigenetic memory earlier stimuli, such as exercise. Long-term retention changes following cancer survival and/or exercise training has not yet been studied. We, therefore, investigated genome-wide DNA methylation (methylome) a 5-month, 3/week aerobic-training intervention breast 10–14 years after diagnosis treatment. These results were compared to who remained untrained age-matched controls with no history cancer, undertook the same intervention. Skeletal biopsies obtained from 23 females before(pre) after(post) 5-month period. InfiniumEPIC 850K arrays RT-PCR for gene expression performed. The displayed significant increased (i.e., hypermethylation) at larger number differentially methylated positions (DMPs) healthy pre training. Training led exaggerated DMPs hypermethylated signature occurring non-regulatory regions controls. However, opposite occurred important regulatory regions, where elicited considerable reduction hypomethylation) 99% located CpG islands within promoter regions. Importantly, was able reverse hypermethylation identified back toward hypomethylated that observed 300 (out 881) these island/promoter-associated CpGs. Pathway enrichment analysis evoked predominantly pathways associated cell cycle, replication/repair, transcription, translation, mTOR signaling, proteosome. Differentially region (DMR) also genes: BAG1, BTG2, CHP1, KIFC1, MKL2, MTR, PEX11B, POLD2, S100A6, SNORD104, SPG7 survivors, reversing DMRs signature. largely different response individuals than very few overlapping changes. Only one gene, SIRT2, having altered baseline both Overall, may retain long treatment/survival. Five months aerobic reset methylome signatures

Language: Английский

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Acetate and succinate benefit host muscle energetics as exercise‐associated post‐biotics

Physiological Reports, Journal Year: 2023, Volume and Issue: 11(21)

Published: Nov. 1, 2023

Abstract Recently, the gut microbiome has emerged as a potent modulator of exercise‐induced systemic adaptation and appears to be crucial for mediating some benefits exercise. This study builds upon previous evidence establishing microbiome‐skeletal muscle axis, identifying changes in composition. Metagenomics sequencing fecal samples from non‐exercise‐trained controls or exercise‐trained mice was conducted. Biodiversity indices indicated exercise training did not change alpha diversity. However, there were notable differences beta‐diversity between trained untrained microbiomes. Exercise significantly increased level bacterial species Muribaculaceae bacterium DSM 103720 . Computation simulation growth used predict metabolites that accumulate under silico culture exercise‐responsive bacteria. We identified acetate succinate potential microbial are produced by , which then administered during period mechanical overload‐induced hypertrophy. Although no observed overall response administration first 5 days hypertrophy, skeletal mitochondrial respiration. When given post‐biotics, treatment may improve oxidative metabolism

Language: Английский

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Exercise-Induced MYC as an Epigenetic Reprogramming Factor That Combats Skeletal Muscle Aging

Exercise and Sport Sciences Reviews, Journal Year: 2024, Volume and Issue: 52(2), P. 63 - 67

Published: Feb. 23, 2024

Of the "Yamanaka factors" Oct3/4 , Sox2 Klf4 and c-Myc (OSKM), transcription factor ( Myc ) is most responsive to exercise in skeletal muscle enriched within fiber. We hypothesize that pulsatile induction of MYC protein after bouts can serve epigenetically reprogram toward a more resilient functional state.

Language: Английский

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SAMD1 suppresses epithelial–mesenchymal transition pathways in pancreatic ductal adenocarcinoma

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(8), P. e3002739 - e3002739

Published: Aug. 13, 2024

Pancreatic ductal adenocarcinoma (PDAC) poses a significant threat due to its tendency evade early detection, frequent metastasis, and the subsequent challenges in devising effective treatments. Processes that govern epithelial—mesenchymal transition (EMT) PDAC hold promise for advancing novel therapeutic strategies. SAMD1 (SAM domain-containing protein 1) is CpG island-binding plays pivotal role repression of target genes. Here, we revealed acts as repressor genes associated with EMT. Upon deletion cells, observed significantly increased migration rates. exerts effects by binding specific genomic targets, including CDH2 , encoding N-cadherin, which emerged driver enhanced upon knockout. Furthermore, discovered FBXO11-containing E3 ubiquitin ligase complex an interactor negative regulator SAMD1, inhibits chromatin-binding genome-wide. High FBXO11 expression poor prognosis EMT-related genes, underlining antagonistic relationship between FBXO11. In summary, our findings provide insights into regulation PDAC, shedding light on intricate interplay this cancer type.

Language: Английский

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Genes encoding agrin (AGRN) and neurotrypsin (PRSS12) are associated with muscle mass, strength and plasma C-terminal agrin fragment concentration

GeroScience, Journal Year: 2023, Volume and Issue: 45(3), P. 1289 - 1302

Published: Jan. 7, 2023

Abstract Although physiological data suggest that neuromuscular junction (NMJ) dysfunction is a principal mechanism underpinning sarcopenia, genetic studies have implicated few genes involved in NMJ function. Accordingly, we explored whether encoding agrin ( AGRN ) and neurotrypsin PRSS12 were associated with sarcopenia phenotypes: muscle mass, strength plasma C-terminal fragment (CAF). PhenoScanner was used to determine if and/or variants had previously been phenotypes. For replication, combined genotype from whole genome sequencing phenotypic 6715 GenoFit participants aged 18–83 years. Dual energy X-ray absorptiometry assessed body lean mass (WBLM) appendicular (ALM), hand dynamometry determined grip ELISA measured CAF subgroup n = 260). Follow-up analyses included eQTL analyses, carrier single-variant gene-burden tests. rs2710873 rs71608359 associate phenotypes, respectively, the UKBB p 8.9 × 10 −6 8.4 cohort 0.019 0.014). are eQTLs for , ≥ three tissues. Compared non-carriers, carriers of 4.0% higher WBLM ALM (both < 0.001), 9.5% lower concentrations while 2.3% 0.034). has further associations Our findings provide novel evidence relevance phenotypes support existing illustrating importance maintaining health during ageing.

Language: Английский

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Effects of high‐resistance wheel running on hallmarks of endurance and resistance training adaptations in mice

Physiological Reports, Journal Year: 2023, Volume and Issue: 11(11)

Published: June 1, 2023

Exercise effectively promotes and preserves cardiorespiratory, neuromuscular, metabolic, cognitive functions throughout life. The molecular mechanisms underlying the beneficial adaptations to exercise training are, however, still poorly understood. To improve mechanistic study of specific adaptations, standardized, physiological, well-characterized interventions are required. Therefore, we performed a comprehensive interrogation systemic changes muscle-specific cellular voluntary low-resistance wheel running (Run) progressive high-resistance (RR) in young male mice. Following 10 weeks training, both groups showed similar improvements body composition peak oxygen uptake (V̇O2peak ), as well elevated mitochondrial proteins capillarization markers M. plantaris. Run mice clearly outperformed RR forced treadmill capacity test, while displayed increased grip strength superior mass gains soleus, associated with distinct proteomic specifying two paradigms. Thus, even though modalities induce overlapping preferably submaximal performance, is valid model training-induced plantar flexor hypertrophy.

Language: Английский

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Depressed Protein Synthesis and Anabolic Signaling Potentiate ACL Tear–Resultant Quadriceps Atrophy

The American Journal of Sports Medicine, Journal Year: 2022, Volume and Issue: 51(1), P. 81 - 96

Published: Dec. 7, 2022

Background: Anterior cruciate ligament (ACL) tear (ACLT) leads to protracted quadriceps muscle atrophy. Protein turnover largely dictates size and is highly responsive injury loading. Regulation of molecular protein synthetic machinery after ACLT has been unexplored, limiting development targeted therapies. Purpose: To define the effect on (1) activation catabolic signaling within biopsy specimens from human participants (2) time course alterations synthesis its regulation in a mouse ACL model. Study Design: Descriptive laboratory study. Methods: Muscle were obtained ACL-injured noninjured vastus lateralis young adult humans an overnight fast (N = 21; mean ± SD, 19 5 years). Mice had their limbs assigned or control, whole collected 6 hours 1, 3, 7 days with puromycin injected before tissue collection for assessment relative synthesis. fiber expression phosphorylation anabolic proteins assessed at transcript levels (RNA sequencing). Results: Human showed reduced ribosomal S6 (–41%) limb ( P .008), addition elevated eukaryotic initiation factor 2α (+98%; .006), indicative depressed injured limb. No differences E3 ubiquitin ligase noted. was lower 1 day .01 vs control limb) 3 .002 mice. Pathway analyses revealed shared between ACLT. Conclusion: Global deficits occur response injury, without notable changes measured markers catabolism. Importantly, these onset significant atrophy, underscoring need early intervention. Clinical Relevance: These findings suggest that blunted anabolism as opposed increased catabolism likely mediates atrophy injury. Thus, future interventions should aim restore rapidly

Language: Английский

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