Comprehensive Physiology Wiley Online Library

State of Knowledge on Molecular Adaptations to Exercise in Humans: Historical Perspectives and Future Directions

Full Article on Wiley Online Library


For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well‐positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise‐induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193‐3279, 2022.

Figure 1. Figure 1. Marie‐Ann Pierrette Lavoisier's sketch depicting her husband Antoine Lavoisier conducting the first exercise physiology experiment and herself taking notes in the right corner. Note the use of the bell‐jar calorimeter and the subject pressing a foot pedal below the table. Reused, with permission, from West JB, 2013 1416.
Figure 2. Figure 2. This figure illustrates an overview of sex‐specific differences in skeletal muscle, the cardiovascular system, and energy metabolism that may be important considerations relevant to human exercise.
Figure 3. Figure 3. This figure illustrates exercise benefits across the lifespan. Normal age‐related changes affect physiological resilience to environmental or genetic stressors, while the susceptibility to metabolic, cardiovascular, and other risk factors increases. Exercise improves multiple functions and physiological indices of wellness. Pie chart slices are greyed out when (i) the physiological index shown is not relevant for a given age (either no longer growing/developing or process has not yet begun to decline) or (ii) the physiological index has not been sufficiently studied in a population at that life stage.
Figure 4. Figure 4. This figure illustrates the range of current and emerging tools in analysis of human tissue for exercise research, with a focus on preparation of blood, skeletal muscle, and adipose tissues (most easily accessed in humans) for downstream high‐throughput ‘omics analyses.
Figure 5. Figure 5. This figure illustrates key skeletal muscle adaptations to aerobic and resistance exercise, highlighting the role of molecular transducers of these effects that are described in the text.
Figure 6. Figure 6. This figure illustrates physiological hypertrophy resulting from exercise training. The long‐term cardiovascular adaptive response depends on the type of hemodynamic stress resulting from the modality of exercise training. Most commonly, aerobic exercise imposes volume overload, leading to eccentric hypertrophy, whereas resistance exercise elicits concentric hypertrophy through pressure overload. Relevant molecular and cellular transducers are explored in the text.
Figure 7. Figure 7. This figure illustrates molecular‐level cross talk between skeletal muscle, adipose tissue, and liver to facilitate energetics during exercise. Key myokines, adipokines, and hepatokines are highlighted.
Figure 8. Figure 8. This figure illustrates simultaneous innervation in skeletal muscle by the somatic and the autonomic nervous systems. Briefly 1104, motor neuron release of acetylcholine (Ach) promotes influx of sodium (Na+) and calcium (Ca++) into skeletal muscle cell. This promotes release of calcium from sarcoplasmic reticulum (SR), leading to contraction. The sympathetic neuron innervates muscle in close proximity and may release norepinephrine (NE) to augment Ach release. Circulating epinephrine from the endocrine system supports sympathetic activation by augmenting Ach release in addition to enhancing Na+ influx and calcium‐induced calcium release and re‐sequestering.
Figure 9. Figure 9. This figure illustrates summary of exercise‐induced adaptations in bone, joint, and tendon; existing knowledge gaps in humans are indicated by question marks (?).
Figure 10. Figure 10. This figure illustrates the range of the impact of exercise on risk factors and pathologies associated with chronic diseases. Exercise is associated with reduced morbidity, lower hospitalization rates, and decreased risk of all‐cause mortality and premature death from disease. Overall, higher cardiorespiratory fitness and a regular exercise training decrease the economic burden of multiple diseases. ↑ indicates increase; ↓ indicates decrease.

Figure 1. Marie‐Ann Pierrette Lavoisier's sketch depicting her husband Antoine Lavoisier conducting the first exercise physiology experiment and herself taking notes in the right corner. Note the use of the bell‐jar calorimeter and the subject pressing a foot pedal below the table. Reused, with permission, from West JB, 2013 1416.

Figure 2. This figure illustrates an overview of sex‐specific differences in skeletal muscle, the cardiovascular system, and energy metabolism that may be important considerations relevant to human exercise.

Figure 3. This figure illustrates exercise benefits across the lifespan. Normal age‐related changes affect physiological resilience to environmental or genetic stressors, while the susceptibility to metabolic, cardiovascular, and other risk factors increases. Exercise improves multiple functions and physiological indices of wellness. Pie chart slices are greyed out when (i) the physiological index shown is not relevant for a given age (either no longer growing/developing or process has not yet begun to decline) or (ii) the physiological index has not been sufficiently studied in a population at that life stage.

Figure 4. This figure illustrates the range of current and emerging tools in analysis of human tissue for exercise research, with a focus on preparation of blood, skeletal muscle, and adipose tissues (most easily accessed in humans) for downstream high‐throughput ‘omics analyses.

Figure 5. This figure illustrates key skeletal muscle adaptations to aerobic and resistance exercise, highlighting the role of molecular transducers of these effects that are described in the text.

Figure 6. This figure illustrates physiological hypertrophy resulting from exercise training. The long‐term cardiovascular adaptive response depends on the type of hemodynamic stress resulting from the modality of exercise training. Most commonly, aerobic exercise imposes volume overload, leading to eccentric hypertrophy, whereas resistance exercise elicits concentric hypertrophy through pressure overload. Relevant molecular and cellular transducers are explored in the text.

Figure 7. This figure illustrates molecular‐level cross talk between skeletal muscle, adipose tissue, and liver to facilitate energetics during exercise. Key myokines, adipokines, and hepatokines are highlighted.

Figure 8. This figure illustrates simultaneous innervation in skeletal muscle by the somatic and the autonomic nervous systems. Briefly 1104, motor neuron release of acetylcholine (Ach) promotes influx of sodium (Na+) and calcium (Ca++) into skeletal muscle cell. This promotes release of calcium from sarcoplasmic reticulum (SR), leading to contraction. The sympathetic neuron innervates muscle in close proximity and may release norepinephrine (NE) to augment Ach release. Circulating epinephrine from the endocrine system supports sympathetic activation by augmenting Ach release in addition to enhancing Na+ influx and calcium‐induced calcium release and re‐sequestering.

Figure 9. This figure illustrates summary of exercise‐induced adaptations in bone, joint, and tendon; existing knowledge gaps in humans are indicated by question marks (?).

Figure 10. This figure illustrates the range of the impact of exercise on risk factors and pathologies associated with chronic diseases. Exercise is associated with reduced morbidity, lower hospitalization rates, and decreased risk of all‐cause mortality and premature death from disease. Overall, higher cardiorespiratory fitness and a regular exercise training decrease the economic burden of multiple diseases. ↑ indicates increase; ↓ indicates decrease.
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