New insights into the molecular basis of how physical activity contributes to human health

Physical exercise is beneficial for maintaining human health. Daily physical activity and balanced nutrition are recommended by the WHO.^1-4 Regular exercise training is recommended at any age and reduces the risk for many chronic metabolic diseases like neurodegenerative and cardiovascular diseases, type 2 diabetes, cancer, and neuronal dysfunctions.^{2, 5} The positive effects of regular exercise include improved insulin sensitivity, increased maximal oxygen uptake, reduced adiposity, less systemic inflammation, and improved bone strength. The underlying molecular biological mechanisms have not yet been fully elucidated.⁴ This report summarizes articles and new research findings about skeletal muscles, physical activity, and its contribution to human health, recently published in Acta Physiologica.

Whether someone is sporty or not depends on many factors. In endurance sports, becoming a successful professional athlete is also hereditary. Kenyan runners belong to the elite middle- and long-distance runners, with Eliud Kipchoge on the top. Kunimasa et al. compared the influence of leg and foot segmental length and muscle–tendon architecture of Kenyans and Japanese males regarding their potential to be an elite middle- and long-distance runner. It was shown that not only Kenyan runners but also the general Kenyan population, compared with the Japanese, have structural advantages in leg composition and muscle–tendon architecture from early childhood.⁶

Athletic performance can be improved via different strategies. One is supplementation with nutritions. Bioactive peptides, like collagen, have systemic beneficial properties, for example, antihypertensive, antimicrobial, immunomodulatory, and antioxidant effects. Balshaw et al. focused on the question whether the supplementation of bioactive collagen peptides, compared with a placebo, improves skeletal muscle strength, size and architecture by resistance training. Therefore, young healthy men underwent a standardized program of resistance training supplemented by either collagen peptides or placebo. They found that on the one hand muscle strength did not increase compared with the control group. On the other hand, resistance training and collagen peptide supplementation positively influenced skeletal muscle remodeling, for example, greater percentage changes in the total volume of muscles exercised, the volume of the quadriceps, and a greater increase in the vastus medialis muscle.⁷

Another method to improve training effects is described by Christiansen et al. Since 2021, a novel popular training method for top athletes is blood-flow-restricted (BFR)-exercise. Muscle blood flow gets reduced by inflating pressure cuffs around the limbs. The research team focused on the question whether BFR exercise could be a potential treatment for metabolic abnormalities like insulin resistance, hyperglycemia and hypercholesterolemia. Therefore, responses of genes involved in cholesterol synthesis, insulin sensitivity, glucose disposal, mitochondrial respiration and network expansion were analyzed in men performing either BFR, systemic hypoxia or normoxia training. In the context of BFR, they observed for example, increased expressions of PGC-1α2 (key role in counteracting cholesterol biosynthesis), GLUT4 (primary glucose transporter in skeletal muscle), and VEGFA (proangiogenic gene), all these promoting the glucose uptake by skeletal muscle fibres. Moreover, the mRNA content of UCP3, a factor for the prognosis of metabolic disease, was increased. In healthy men, BFR in exercise has the potential to show in an early stage the exercise-induced molecular adaptations that are responsible for the improvement of metabolic health. Whether BFR exercise is a treatment option for patient with metabolic complications needs to be further elucidated in patient populations.⁸

Children often live out their natural urge to be physically active. Eftestøl et al. showed in experiments with rats how beneficial it is to exercise at a young age.⁹ Four-week-old rats underwent 5 weeks of climbing training compared with a control group. This was followed by a 10-week training break and then another 3 weeks of training. The muscle fibre cross-sectional area (fSCA), the amount of myonuclei, and the body weight were analyzed. The rats that had the climbing training at a young age showed a muscle memory effect. In adult animals, the fCSA level was 16% higher in the second training phase than in the animals of the control group. Furthermore, these rats were leaner and body weight was decreased, indicating a body weight memory, as all rats were fed ad libitum. During the training break, the fSCA value dropped, but the number of myonuclei was stable. The constant number of myonuclei could be causative for the muscle memory. The half-life of extracted human myonuclei is about 15 years, suggesting that such a memory effect in humans could be very long-lasting.⁹

Even the parents' sporting behavior has a positive effect on the physiology of the offspring. Exercise as an intervention for mothers or fathers before conception has a beneficial effect on the health of the offspring. While many studies have analyzed the influence of physical activity of pregnant women on the unborn child, evidence is now accumulating that the father's lifestyle also has an influence. In their review, Sousa Neto et al. give a comprehensive overview about the published effects of a healthy lifestyle of fathers on the offspring.² On the molecular level, beneficial modifications of chromatin, histones, and DNA take place and thus influence epigenetics. Non-coding RNAs are also involved in the regulation of epigenetic processes. Furthermore, the sperm quality is positively influenced by physical activity of the man. On a physiological level, various training programs of the fathers open up positive effects on the offspring: in the nervous system, for example, spatial learning and memory capability, endocrine system, urinary system, fat tissue, for example, decreased adiposity markers, blood circulation, cardiovascular system, and musculoskeletal system.

Nevertheless, it is never too late to exercise. Physical activity is recommended at any age.² Frandsen et al. investigated the effects of extreme endurance training on young and older men in terms of whether there is an upper limit to the health benefits of extreme exercise. Subjects aged 30 ± 5 years and 65 ± 6 years cycled about 3000 km in 15 days. Various adaptive metabolic effects were investigated, and many positive effects were determined in both groups: a decrease in mitochondrial ROS production and fat oxidation, an increase in skeletal muscle mass, and an improved glucose homeostasis. However, for cardiorespiratory fitness differences between the young and the old occurred. In the older cohort, the maximum oxygen uptake shows a decrease, as well as the maximal heart rate and the handgrip strength, but this is all not seen in the younger group. This negative effect on the cardiovascular system in older men could be explained by a greater ability of younger men to achieve the maximal heart rate. Also blood hemoglobin levels reach baseline faster in younger than in older participants.⁵

Unfortunately, aging goes along with muscle atrophy. Loss of muscle mass, called sarcopenia, leads to negative health outcomes, first and foremost physical restrictions. With increasing numbers of older adults worldwide, it is not surprising that age-related decline in muscle mass, strength, and function has become a major global health concern. Leduc-Gaudet et al. mention in their review that one promising target to prevent skeletal muscle dysfunction is to enhance mitophagy in the skeletal muscle.¹ The first study dealing with the influence of muscles and mitochondria was published in 1939.¹⁰ Since then, there have been many new findings at the molecular level, for example, that the mitochondrial permeability transition pore (mPTP) becomes dysfunctional in rodents and humans due to aging. This has been shown to contribute to age-related loss of muscle mass and function, for example, through mitochondrial ROS overproduction. Positively, studies prove that physical activity does not only improve muscle and mitochondrial health but also stimulates mitophagy.¹

Even in individuals suffering from Parkinson's disease, physical exercise can have beneficial effects. Muscular deficiency occurs in a similar way in Parkinson's patients, as well as in healthy people of the same age. A decrease in muscle strength can result from neural as well as muscular alterations. Martignon et al. showed that most likely increasing skeletal muscle contractility via physical activity counterbalances the neuromuscular deterioration in Parkinson's disease patients. However, to recognize performance-limitating factors and to generate a suitable training plan for patients suffering from Parkinson's disease the neuromuscular prerequisites need to be identified and considered.¹¹

Skeletal muscle atrophy causes a shift toward protein catabolism in the muscle. Cross talk between immune cells and skeletal muscles contributes to protein degradation, resulting in a loss of muscle mass, strength, and functional capacity. In their review, Padilha et al. focus on the question how physical exercise promotes immunometabolism in disused muscles, for example, because of bed rest or space flight.¹² Immunometabolic changes in muscle due to disuse refer to responses from macrophages and T cells in tissues and further circulating immune cells and pro-inflammatory cytokines. After physical exercise following an interval of disuse, an arsenal of M2 macrophages, Treg cells, anti-inflammatory cytokines, and catecholamines contribute to protein synthesis for muscle remodeling. Physical exercise always helps to attenuate the harmful effect of muscle disuse, although no specific strategy to improve muscle strength and mass was identified. However, the authors emphasize the participation of hospitalized patients and astronauts in exercise programs to counteract negative immunometabolic responses.¹²

Besides immune responses, endocrine organs regulate major systemic impacts resulting from exercise. Tissue cross talk takes place via known potential mediators, which are called exerkines.¹³ Exerkines comprise myokines from the skeletal muscle, cytokines, and proteins from the liver and adipose tissue⁴ and microRNAs (miRNA). Myokines are, for example, IL6, IL15, growth differentiation factor 15 (Gdf15), Irisin, and Myostatin. One of the first identified and best-studied myokines is IL6, which is known as a pro-inflammatory cytokine of the adaptive immune system. In response to acute exercise, IL6 mRNA levels in muscle and fat increase, and in circulating levels, IL6 increases up to 100-fold. However, the underlying molecular mechanisms, how IL6 works as a myokine, remain unclear. Most likely, there is cross talk between skeletal muscles and liver and adipose tissue to increase glucose production.⁴

In this context, extracellular vesicles (EVs) that were found to carry potent exerkines need to be mentioned.^{3, 4} Doncheva et al. analyzed EVs that are induced by physical exercise. Therefore, dysglycemic and normoglycemic sedentary men with or without overweight performed a 12-week endurance and strength exercise. Adipose tissue was measured, and EVs were isolated from plasma. For the test persons, 12 weeks of training caused an increase in insulin sensitivity and reduced fat mass. It remains unclear, where the origin of the isolated EVs is but it is likely that various cell types are involved, for example, leukocytes, mast cells, epithelial cells, and muscle cells. The amount of miRNAs within the EVs increased in response to acute exercise. Several of these miRNAs have a connection to insulin sensitivity and adiposity or muscle cell and myoblast proliferation.³

In another recent study, researchers analyzed the role of the protein Sestrin2 (SESN2) for exercise metabolism. They used SESN2 −/− mice to find out whether SESN2 is required for exercise-induced browning of white adipose tissue. SESN2 belongs to a family of stress-inducible proteins for the regulation of metabolic homeostasis. They found SESN2 to be a key protein for establishing exercise-induced metabolic benefits. Removal of SESN2 reduced the maximum oxygen uptake, energy consumption, and the average exchange ratio of airways during exercise. SESN2 was found to play an important role by promoting browning of white adipose tissue and the overall improvement of energy metabolism due to exercise.¹⁴

Cellular protein content is regulated by the endoplasmic reticulum (ER), which is responsible for protein translation, post-translational folding, protein modification, and protein complex formation. More than half of all proteins in the human organism are contained in skeletal muscle. Among other things, physical exercise causes ER stress.¹⁵ Marafon et al. describe in their review how the unfolded protein response (UPR) is activated in response to ER stress via three transmembrane proteins (IRE1α, PERK, and ATF6α). Acute physical exercise always leads to ER stress and activates UPR, which then maintains homeostasis. Excessive training load and insufficient rest result in pathological ER stress. However, regular moderate-intensity exercise has the potential to positively attenuate the ER-stress-related responses of genes and proteins.¹⁶

Researchers also speculated that ribosome biogenesis is related to resistance training.¹⁷ Hammarström et al. now analyzed the effect of resistance training on ribosome biogenesis, focusing on the time course.¹⁸ Muscle thickness, total RNA, ribosomal RNA, ribosomal protein S6, and upstream binding factor were analyzed at six different time points within 12 days and after 8 days of detraining for a group practicing resistance training and a control group. Training-induced muscle hypertrophy as seen in increased muscle growth occurred. Moreover, there are increases in total RNA associated with upstream binding factor protein level, ribosomal RNA, and ribosomal protein S6. Especially in the initial phase, within the first four sessions of training an accumulation of ribosomes appeared, followed by a plateau phase of ribosome synthesis. After detraining, muscle mass remained unchanged, but the level of total RNA decreased, indicating that ribosome biogenesis is interrupted after cessation of training.^{18, 19}

In sum, the new comprehensive knowledge about skeletal muscle in terms of training age, training mode, genetics, epigenetics, and communication with other human organs at the molecular level provides a good basis for the development of therapeutic training plans and therapeutics against many diseases, for example, chronic metabolic and neurodegenerative diseases.

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