Summary: New research shows that exercise produces epigenetic changes that promote a more youthful molecular profile in aging organisms.
Source: University of Arkansas
A recent paper in the Journal of Physiology strengthens evidence that exercise preserves youth-like molecular features in aged tissues. The study builds on earlier work in which older mice given access to a weighted running wheel showed improved markers of muscle health and resilience.
The detailed study, titled “A molecular signature defining exercise adaptation with aging and in vivo partial reprogramming in skeletal muscle,” lists 16 co-authors, six of whom are affiliated with the University of Arkansas.
The corresponding author is Kevin Murach, an assistant professor in the Department of Health, Human Performance and Recreation at the University of Arkansas. The first author is Ronald G. Jones III, a Ph.D. student in Murach’s Molecular Muscle Mass Regulation Laboratory.
In this work, the team directly compared three models: aged mice that exercised on a weighted wheel late in life, aged mice in which muscle cells were genetically induced to express the four Yamanaka reprogramming factors, and mice engineered to overexpress just the Myc factor in muscle.
The Yamanaka factors—Oct3/4, Sox2, Klf4 and c-Myc (often abbreviated OKSM)—are transcription factors known to revert specialized cells to a more stem-like, flexible state. Nobel Prize–winning work by Dr. Shinya Yamanaka in 2012 identified these factors, and controlled expression of the factors in animals can partially reverse features associated with aging by restoring some cellular adaptability.
Notably, Myc is the OKSM factor most strongly induced by contracting skeletal muscle. Because Myc rises with exercise, the researchers used it as a point of comparison between genetic partial reprogramming (OKSM overexpression) and the natural, activity-driven reprogramming that occurs with exercise. Here, “reprogramming” refers to changes in gene accessibility and expression driven by external stimuli such as physical activity.
Comparing transcriptional and epigenetic profiles across these models, the team found that late-life exercise promotes a molecular signature consistent with partial epigenetic reprogramming. In other words, exercise induces a gene-expression and DNA-methylation pattern in aged skeletal muscle that resembles—at least in part—the pattern observed after OKSM-induced reprogramming.
The study suggests that some of exercise’s beneficial effects on aged muscle may be mediated by Myc. However, the authors caution against the simplistic idea that manipulating Myc alone could replace the broad, systemic benefits of physical activity.
Murach emphasizes two important caveats. First, Myc cannot replicate the full range of exercise’s systemic effects, which include changes in metabolism, circulation, inflammation, and signaling across multiple organs. Second, Myc has well-known links to tumor formation—overactivation carries oncogenic risk—so directly targeting Myc would require extreme caution.
Rather than serving as a shortcut to replace exercise, experimental manipulation of Myc may be most useful as a research tool to understand how to restore exercise responsiveness in aged muscle that has become less adaptable. It might also inform approaches to safely boost exercise-like benefits for people who cannot perform vigorous activity—such as astronauts in microgravity or patients confined to prolonged bed rest—if researchers can isolate the advantageous, non-harmful effects of Myc signaling.
Overall, the authors frame their findings as additional support for the idea of exercise as a broadly effective therapeutic intervention. “Exercise is the most powerful drug we have,” Murach notes, and it remains a critical, evidence-based component of healthy aging alongside proper nutrition and appropriate medical care.
About this exercise, genetics, and aging research news
Author: Press Office
Source: University of Arkansas
Contact: Press Office – University of Arkansas
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Original Research: Closed access.
“A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle” by Ronald G. Jones et al., Journal of Physiology
Abstract
A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle
Exercise produces measurable functional benefits in aged tissues, but it has been unclear to what degree those benefits reflect a form of partial molecular reprogramming. To address this, the authors combined transcriptome and epigenome profiling from multiple models: 1) a muscle-specific in vivo model expressing the four reprogramming factors Oct3/4, Klf4, Sox2 and Myc (OKSM); 2) an inducible, muscle-specific in vivo Myc induction model; 3) a translatable high-volume hypertrophic exercise training protocol applied to aged mice; and 4) muscle biopsies from humans with habitual exercise.
Late-life exercise training reduced murine DNA methylation age using several contemporary muscle-specific epigenetic clocks. Comparing the soleus muscle transcriptome after late-life exercise with the transcriptome following OKSM induction revealed an overlapping signature, including increased JunB and Sun1 expression. Within this shared signature, select mitochondrial and muscle-enriched genes were downregulated; a similar pattern appeared in long-term exercise-trained human skeletal muscle, including reduced expression of the muscle-specific Abra/Stars gene.
Myc was the OKSM factor most strongly induced by exercise in muscle and remained elevated after exercise training in aged mice. A brief pulse of Myc altered the global methylation landscape of soleus muscle, and the transcriptomic response to a Myc pulse partially recapitulated the effects of OKSM induction. A common gene set also emerged between Myc-driven changes and exercise adaptation, such as lower muscle-specific Melusin and the reactive-oxygen-species-associated gene Romo1.
Across Myc, OKSM, and exercise models in mice—and in habitual exercise conditions in humans—the complex I accessory subunit Ndufb11 was consistently lower; reduced Ndufb11 has been associated with longevity in rodent studies. Taken together, these results indicate that exercise shares molecular similarities with in vivo partial reprogramming and that Myc contributes to, but does not fully account for, exercise-induced rejuvenation-like signatures in skeletal muscle.