Search

The objectives of this study were to measure to what extent exercise stimulates partial molecular reprogramming in skeletal muscle. We hypothesized that exercise training, beyond its known functional improvements in aged tissues, could recapitulate some of the same effects that are seen with in vivo partial reprogramming by Yamanaka factors. Using transcriptome profiling from 1) a skeletal muscle-specific in vivo Oct3/4, Klf4, Sox2, and Myc (OKSM) reprogramming-factor expression murine model, 2) an in vivo inducible muscle-specific Myc induction murine model, 3) a translatable high-volume hypertrophic exercise training approach in aged mice, and 4) human exercise muscle biopsies, we collectively defined exercise-induced genes common to partial reprogramming. Late-life exercise training lowered murine DNA methylation age according to several contemporary muscle-specific clocks. A comparison of the murine soleus transcriptome after late-life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature. Within this signature, downregulation of specific mitochondrial and muscle-enriched genes was conserved in skeletal muscle of long-term exercise-trained humans; among these was muscle-specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC-controlled and exercise adaptation transcriptomes, including lower muscle-specific Melusin and reactive oxygen species-associated Romo1. With Myc, OKSM, and exercise training in mice as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Our data collectively suggest: 1) a biological age-mitigating effect on the epigenetic landscape by late-life exercise-training in murine skeletal muscle, 2) a common gene expression signature of partial reprogramming by OKSM and exercise training in muscle of humans and aged mice, and 3) that Myc is an exercise-responsive factor that contributes to a rewired molecular profile at the transcriptome and methylome levels. National Institutes of Health: Kevin A. Murach, AG063994; American Federation for Aging Research (AFAR): Kevin A. Murach, Junior Investigator Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Skeletal muscle adaptation during conditions of dynamic muscle loading such as resistance-type exercise occurs in conjunction with pronounced changes in gene expression. The objective of this study was to comprehensively evaluate gene expression at the onset of rapid muscle hypertrophy in mice. We analyzed the global, nascent, stable, and myonuclear transcriptome utilizing RNA-sequencing. C57BL6/J mice were treated with 5-ethenyl uridine at the end of 72 hours of synergist ablation mechanical overload of the plantaris muscle to assess transcriptional dynamics; sham mice served as controls. Mice with in vivo fluorescent myonuclear labeling were used to obtain RNA-sequencing in exclusively myonuclei from overloaded and sham mice. In these analyses, RUNX family transcription factor 1 ( Runx1, or Aml1) was significantly elevated in all conditions (adj. p This work is supported by the National Institutes of Health under grant R00 AG063994 to Kevin A. Murach. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cancer cachexia (CC) affects up to 80% of cancer patients and is responsible for 20-40% of cancer related deaths. Our laboratory recently demonstrated that emission of muscle mitochondrial reactive oxygen species (ROS) is highly elevated shortly after the onset of tumor-bearing in mice. Therefore, targeting of mitochondrial ROS may be a viable option to treat and prevent CC. The aim of this study was to evaluate the effectiveness of a mitochondria-targeted antioxidant, SkQ1, at preventing CC. We hypothesized SkQ1 prevents muscle atrophy and weakness in tumor-bearing mice. To test the effect of SkQ1 on CC, female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells to the hind flanks for a total cell volume of 1x106, while equal volume of PBS was injected in a separate cohort as a sham control. SkQ1 was dissolved in drinking water (250 nmol/kg body weight/day) and administered to mice, while control groups drank normal drinking water. Body weight was assessed every 5 days. In vivo muscle contractility and fatigability were assessed via electrophysiological measurements two days prior to endpoint. At the endpoint (~25 days after C26/PBS injections) body weight and tissue wet weights were measured and normalized by tibia length (mg/mm). Data were analyzed by 2X2 ANOVA with Tukey’s post hoc test where significant interactions were found with p≤0.05. C26 mice had lower tumor-free body weight (p This study was supported by the National Institutes of Health Award Number 5R01AR075794-02. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.