Muscle memory in humans: evidence for myonuclear permanence and long-term transcriptional regulation after strength training.

The objective of this work was to investigate myonuclear permanence and transcriptional regulation as mechanisms for cellular muscle memory after strength training in humans. Twelve untrained men and women performed 10 weeks of unilateral elbow-flexor strength training followed by 16 weeks of de-training. Thereafter, 10 weeks' re-training was conducted with both arms: the previously trained arm and the contralateral untrained control arm. Muscle biopsies were taken from the trained arm before and after both training periods and from the control arm before and after re-training. Muscle biopsies were analysed for fibre cross-sectional area (fCSA), myonuclei and global transcriptomics (RNA sequencing). During the first training period, myonuclei increased in type 1 (13 ± 17%) and type 2 (33 ± 23%) fibres together with a 30 ± 43% non-significant increase in mixed fibre fCSA (P = 0.069). Following de-training, fCSA decreased in both fibre types, whereas myonuclei were maintained, resulting in 33% higher myonuclear number in previously trained vs. control muscle in type 2 fibres. Furthermore, in the previously trained muscle, three differentially expressed genes (DEGs; EGR1, MYL5 and COL1A1) were observed. Following re-training, the previously trained muscle showed larger type 2 fCSA compared to the control (P = 0.035). However, delta change in type 2 fCSA was not different between muscles. Gene expression was more dramatically changed in the control arm (1338 DEGs) than in the previously trained arm (822 DEGs). The sustained higher number of myonuclei in the previously trained muscle confirms myonuclear accretion and permanence in humans. Nevertheless, because of the unclear effect on the subsequent hypertrophy with re-training, the physiological benefit remains to be determined. KEY POINTS: Muscle memory is a cellular mechanism that describes the capacity of skeletal muscle fibres to respond differently to training stimuli if the stimuli have been previously encountered. This study overcomes past methodological limitations related to the choice of muscles and analytical procedures. We show that myonuclear number is increased after strength training and maintained during de-training. Increased myonuclear number and differentially expressed genes related to muscle performance and development in the previously trained muscle did not translate into a clearly superior responses during re-training. Because of the unclear effect on the subsequent hypertrophy and muscle strength gain with re-training, the physiological benefit remains to be determined.

Cytotoxic T-cells mediate exercise-induced reductions in tumor growth.

Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent antitumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their antitumoral efficacy.

Exercise affects almost all tissues in the body, and scientists have found that being physically active can reduce the risk of several types of cancer as well as improving outcomes for cancer patients. However, it is still unknown how exercise exerts its protective effects. One of the hallmarks of cancer is the ability of cancer cells to evade detection by the immune system, which can in some cases stop the body from eliminating tumor cells. Rundqvist et al. used mice to investigate how exercise helps the immune system act against tumor progression. They found that when mice exercised, tumor growth was reduced, and this decrease in growth depended on the levels of a specific type of immune cell, the CD8+ T cell, circulating in the blood. Additionally, Rundqvist et al. found that CD8+ T cells were made more effective by molecules that muscles released into the blood during exercise. Isolating immune cells after intense exercise showed that these super-effective CD8+ T cells alter how they use molecules for energy production after exertion. Next, immune cells from mice that had exercised frequently were transferred into mice that had not exercised, where they were more effective against tumor cells than the immune cells from untrained mice. These results demonstrate that CD8+ T cells are altered by exercise to improve their effectiveness against tumors. The ability of T cells to identify and eliminate cancer cells is essential to avoid tumor growth, and is one of the foundations of current immune therapy treatments. Exercise could improve the outcome of these treatments by increasing the activation of the immune system, making tumor-fighting cells more effective.

Modulation of exercise training related adaptation of body composition and regulatory pathways by anabolic steroids.

Anabolic steroids have a long history of abuse in amateur and professional athletics. However, their interaction with training and the resulting effects on body composition and tissue adaptation, relying on a concert of factors and pathways, remain under investigation. This study aims at investigating the changes of body composition and the expression of selected genes and pathways essential for this adaptation process. Therefore, male wistar rats were treated with the anabolic steroid metandienone in two groups (n = 16; metandienone, metandienone + exercise) alongside with control groups (n = 16; control, exercise). Following a 6-week steep-angle treadmill training protocol, weight of organs, visceral fat and muscles was determined. M. gastrocnemius was histologically assessed by ATPase staining, mRNA and protein levels of factors of regeneration, hypertrophy and myogenesis and selected master regulators and markers were determined. Results show additive effects of anabolic steroids and exercise on body, tibia and reproductive organs weight. Mm. gastrocnemius and soleus weight was increased by training but not anabolic steroids. Muscle fiber diameter and composition remained unchanged. Visceral fat mass and fat cell size was affected by training and anabolic steroids but no additive effects could be observed. Exercise and anabolic steroids result in a complex regulation of the expression of genes in M. Gastrocnemius involved in skeletal muscle metabolism, hypertrophy, inflammation and regeneration. In summary, our data suggests distinct molecular mechanisms involved in the adaptation of the skeletal muscle to anabolic androgenic steroids and exercise. Metandienone treatment neither results in skeletal muscle hypertrophy nor liver-toxic effects but in an induction of skeletal muscle regeneration and an activation of endocrine negative feedback. Moreover our study demonstrates that visceral fat and bone responds with higher sensitivity to ASS and exercise than the skeletal muscle. This apparent plasticity of adipose and bone tissue rather than skeletal muscle could indicate a potentially superior future role of fat rather than muscle related parameters to detect and AAS abuse in a biologic passport strategy in professional athletes.