Exercise, in the form of endurance or resistance training, leads to specific molecular and cellular adaptions not only in skeletal muscles, but also in many other organs such as the brain, liver, fat or bone. These adaptations are mediated by the production and release of signaling molecules, myokines, from skeletal muscle. Most studies have so far focused on the regulation and function of such myokines in acute exercise bouts. In contrast, unraveling which of the acutely secreted factors are involved in mediating local and systemic adaptations to long-term training has received much less attention.

This review summarizes the current knowledge about secreted factors stimulated by endurance and/or resistance exercise that are contributing to long-term training adaptations.

Endurance and resistance exercise elicit distinct but also overlapping training responses. The authors discussed these molecular responses separately.

The molecular adaptations to endurance exercise involve the changes in production and secretion of myokines such as IL-6, IL-8, VEGF, musclin, BNP, apelin, myonectin, BDNF, neurturin and others. In addition, a number of mitochondrial-derived peptides, microRNAs factors secreted by resident or infiltrating cells in skeletalmuscle take part in forming the long-term adaptive response to endurance training.

IL-6 is known to serve primarily as a metabolic coordinator during acute exercise bouts by regulating lipolysis in adipose tissue. IL-6-driven lipolysis during acute exercise bouts may lead to improved body composition following endurance training over time. IL-6 is further known for its anti-inflammatory effects in both acute exercise bouts and exercise training. This myokine may further be involved in endurance training-induced cardiac remodeling.

IL-8 is primarily known for its angiogenic activity and role as a chemoattractant in inflammatory processes. The potentially pro-angiogenic effects of IL-8 on capillarization are likely to be dose-dependent and perhaps require the pulsatile nature of exercise training.

Vascular endothelial growth factor (VEGF) is among the most important pro-angiogenic factors in many tissues. Muscle fibers are thought to autonomously react to the stresses induced by exercise by secreting VEGF, which leads to enhanced capillarization following training and thereby facilitated energy substrate and oxygen supply as well as byproduct removal.

Brain natriuretic peptide (BNP) is mainly produced by cardiomyocytes in cardiac ventricles upon stretch to initiate signaling events that reduce blood pressure and blood volume.

Another factor, BDNF, has been consistently reported to increase in the circulation in response to exercise. Many chronic diseases including type 2 diabetes and cardiovascular disease are associated with lowercirculating BDNF levels and can be mitigated with exercise interventions.

The functions of other factors mentioned earlier in the long-term adaptations require further investigations, as most of the available evidence are indirect or obtained in various models.

The role and relative contribution of the majority of factors is poorly understood, even for the most extensively studied molecules. For instance, it is not clear whether the IL-6-related long-term adaptations are in fact due to muscle-secreted IL-6, as other organs could contribute to the systemic increase during exercise. Furthermore, there is no evidence of sustained or enhanced IL-6 myokine production and release in endurance-trained muscle, implying that if long-term effects are mediated by muscle IL-6, they would be the consequences of repeated acute elevation and related signaling.

Similarly, plasma BNP increases in response to exercise, but the relative contribution of different tissues to this increase is not exactly known.

Factors secreted by skeletal muscle fibers in response to resistance training could play a key role in modulating neuromuscular plasticity in response to resistance training. The review discussed the functions and contribution of IGF-1, VEGF, myostatin, follistatin, decorin, matrix metalloproteinases (MMPs, particularly MMP-2), SPARC, IL-6, and IL-8.

Similar to the factors involved in the responses to endurance training, the role of the factors secreted during the resistance training is not fully understood. For instance, IGF-1 is an extensively studied regulator of muscle growth, differentiation and regeneration. However, the relative contribution of skeletal muscle-derived IGF-1 to the systemic increase in response to resistance exercise has yet to be assessed.

The authors noted that, for almost all factors, data are scarce, and it often is not clear whether the relative and absolute levels, release and elimination kinetics, or other parameters are indeed changed in response to training in humans. It is conceivable that the repeated release of secreted factors and their downstream signaling over time contribute to training adaptation in a cumulative manner.

Studies in human volunteers is hampered by the difficulty to track the source of secreted factors, and thus attribution to myokine action remains elusive since most of these factors are also produced by other cell types and tissues. Moreover, circulating concentrations often are very low, and therefore, conventional detection methods, might not be sufficiently sensitive, produce unspecific and unreliable results, or might not even exist.

Besides these challenges in discovery and validation, the potential therapeutic exploitation of myokines faces several obstacles. Among those, issues with stability, immunogenicity and toxicity as well as achieving cell- and/or tissue-specific targeting to avoid side effects are key limitations. If successfully overcome, however, myokines have an enormous potential. Targeting these factors and leveraging their functions could not only have broad implications for athletic performance, but also for the prevention and therapy in diseased and elderly populations.

 

Source:

Leuchtmann AB et al. (2021) The Role of the Skeletal Muscle Secretome in Mediating Endurance and Resistance Training Adaptations. Front. Physiol. 12:709807.

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