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Resistance Exercise, Aging, Disuse, and Muscle Protein Metabolism

James McKendry, Tanner Stokes, Jonathan C. Mcleod, Stuart M. Phillips

10.1002/cphy.c200029

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

Skeletal muscle is the organ of locomotion, its optimal function is critical for athletic performance, and is also important for health due to its contribution to resting metabolic rate and as a site for glucose uptake and storage. Numerous endogenous and exogenous factors influence muscle mass. Much of what is currently known regarding muscle protein turnover is owed to the development and use of stable isotope tracers. Skeletal muscle mass is determined by the meal‐ and contraction‐induced alterations of muscle protein synthesis and muscle protein breakdown. Increased loading as resistance training is the most potent nonpharmacological strategy by which skeletal muscle mass can be increased. Conversely, aging (sarcopenia) and muscle disuse lead to the development of anabolic resistance and contribute to the loss of skeletal muscle mass. Nascent omics‐based technologies have significantly improved our understanding surrounding the regulation of skeletal muscle mass at the gene, transcript, and protein levels. Despite significant advances surrounding the mechanistic intricacies that underpin changes in skeletal muscle mass, these processes are complex, and more work is certainly needed. In this article, we provide an overview of the importance of skeletal muscle, describe the influence that resistance training, aging, and disuse exert on muscle protein turnover and the molecular regulatory processes that contribute to changes in muscle protein abundance. © 2021 American Physiological Society. Compr Physiol 11:2249‐2278, 2021.

Figure 1. Figure 1. Schematic representation of the main differences between using acute infused stable isotope tracers and ingested deuterium oxide (D2O) for assessing muscle protein turnover. This figure also depicts how stable isotope tracers are incorporated into metabolic substrates/tissues and detected using mass spectrometry. Modified, with permission, from Wilkinson DJ, et al., 2016 295.
Figure 2. Figure 2. Exogenous and endogenous variables that can influence skeletal muscle hypertrophy. Resistance exercise‐ and nutrition‐related variables such as dietary protein are considered to be the most reliable exogenous variables for skeletal muscle hypertrophy. Endogenous variables are affected by exogenous variables, and modifications to histones, transcription factors, satellite cells, and/or androgen receptor content are thought to be key determinants of skeletal muscle hypertrophy. Modified, with permission, from Joanisse S, et al., 2020 125.
Figure 3. Figure 3. A simplified schematic of the molecular pathways that affect changes in skeletal muscle mass. Resistance training leads to numerous homeostatic perturbations that are sensed by skeletal muscle and initiate a cascade of signaling events and important molecular processes, including protein synthesis and degradation, that underpin skeletal muscle mass. Here, simplified linear pathways are shown, but these pathways undoubtedly have a degree of dependence, crosstalk, interference, and redundancy in their regulation.
Figure 4. Figure 4. Signaling pathway depicting the regulation of ribosome biogenesis (translational capacity) purported to underpin changes in skeletal muscle hypertrophy. The assembly of the preinitiation complex, active rRNA genes are transcribed and processed to form ribosomal subunits, and the subsequent export of the mature ribosome to carry out protein synthesis. Modified, with permission, from Figueiredo VC and McCarthy JJ, 2019 80.
Figure 5. Figure 5. Muscle protein accretion only occurs during periods of positive net protein balance (NBAL) [i.e., when rates of muscle protein synthesis (MPS; blue line) exceed that of muscle protein breakdown (MPB; red line)]. In response to resistance training (RT) in the fasted state, rates of MPS and MPB increase, and MPB exceeds MPS resulting in a negative net protein balance (NBAL). Whereas, following RT in the fed state, MPS is increased to a greater extent and MPB is suppressed resulting in a positive NBAL. This figure shows how chronic RT modifies the RT‐induced changes in MPS and MPB in the fasted and fed state. Dash‐dotted lines indicate fasted rates of MPS (blue) and MPB (red), dashed lines indicate RT‐induced changes in MPS (blue) and MPB (red) in the fasted state, solid lines reflect RT‐induced changes in MPS (blue) and MPB (red) in the fed state. Gray shaded areas reflect periods of positive NBAL. Adapted, with permission, from Joanisse S, et al., 2020 125.
Figure 6. Figure 6. Muscle protein synthesis (MPS) and muscle protein breakdown (MPB) in responses to typical daily feeding patterns in the older individuals. Solid blue lines reflect MPS and the dashed red lines reflect MPB. Blue dashed areas reflect periods of positive net protein balance (NBAL) and red dotted areas reflect periods of negative NBAL. Adapted, with permission, from Oikawa SY, et al., 2019 200.
Figure 7. Figure 7. Schematic representation of the factors that contribute to the development of anabolic resistance of protein synthesis with aging.
Figure 8. Figure 8. Resistance exercise is a potent stressor that activates numerous signaling cascades within skeletal muscle. However, many of these signaling events are generic features of exercise, and so are also seen with aerobic training. Recent evidence has shown that exercise‐induced changes in mitochondrial, extracellular matrix (ECM), and angiogenesis‐related gene expression play an important role in muscle growth with resistance exercise training. Importantly, rather than functioning in isolation, these genes are members of hierarchical networks that interact to bring about changes in phenotype (i.e., muscle hypertrophy). These interactions are difficult to model using low‐throughput analytical techniques. The figure shows two trajectories: higher responders and lower responders. Higher responders activate the genes shown in the gears, which leads to muscle hypertrophy. Lower responders have some sort of block (represented in the figure as a crowbar preventing the gears from turning), perhaps inflammation, that may prevent sufficient activation of these gene networks, leading to negligible hypertrophy.
Figure 9. Figure 9. Muscle disuse is associated with an early reduction in mitochondrial transcripts and protein abundance that precedes and may drive, alterations in gene expression related to protein metabolism (i.e., synthesis and breakdown‐related genes/proteins). Solid black arrows depict known relationships, whereas dotted blue arrows depict hypothetical relationships based predominantly on evidence from preclinical models.


Figure 1. Schematic representation of the main differences between using acute infused stable isotope tracers and ingested deuterium oxide (D2O) for assessing muscle protein turnover. This figure also depicts how stable isotope tracers are incorporated into metabolic substrates/tissues and detected using mass spectrometry. Modified, with permission, from Wilkinson DJ, et al., 2016 295.


Figure 2. Exogenous and endogenous variables that can influence skeletal muscle hypertrophy. Resistance exercise‐ and nutrition‐related variables such as dietary protein are considered to be the most reliable exogenous variables for skeletal muscle hypertrophy. Endogenous variables are affected by exogenous variables, and modifications to histones, transcription factors, satellite cells, and/or androgen receptor content are thought to be key determinants of skeletal muscle hypertrophy. Modified, with permission, from Joanisse S, et al., 2020 125.


Figure 3. A simplified schematic of the molecular pathways that affect changes in skeletal muscle mass. Resistance training leads to numerous homeostatic perturbations that are sensed by skeletal muscle and initiate a cascade of signaling events and important molecular processes, including protein synthesis and degradation, that underpin skeletal muscle mass. Here, simplified linear pathways are shown, but these pathways undoubtedly have a degree of dependence, crosstalk, interference, and redundancy in their regulation.


Figure 4. Signaling pathway depicting the regulation of ribosome biogenesis (translational capacity) purported to underpin changes in skeletal muscle hypertrophy. The assembly of the preinitiation complex, active rRNA genes are transcribed and processed to form ribosomal subunits, and the subsequent export of the mature ribosome to carry out protein synthesis. Modified, with permission, from Figueiredo VC and McCarthy JJ, 2019 80.


Figure 5. Muscle protein accretion only occurs during periods of positive net protein balance (NBAL) [i.e., when rates of muscle protein synthesis (MPS; blue line) exceed that of muscle protein breakdown (MPB; red line)]. In response to resistance training (RT) in the fasted state, rates of MPS and MPB increase, and MPB exceeds MPS resulting in a negative net protein balance (NBAL). Whereas, following RT in the fed state, MPS is increased to a greater extent and MPB is suppressed resulting in a positive NBAL. This figure shows how chronic RT modifies the RT‐induced changes in MPS and MPB in the fasted and fed state. Dash‐dotted lines indicate fasted rates of MPS (blue) and MPB (red), dashed lines indicate RT‐induced changes in MPS (blue) and MPB (red) in the fasted state, solid lines reflect RT‐induced changes in MPS (blue) and MPB (red) in the fed state. Gray shaded areas reflect periods of positive NBAL. Adapted, with permission, from Joanisse S, et al., 2020 125.


Figure 6. Muscle protein synthesis (MPS) and muscle protein breakdown (MPB) in responses to typical daily feeding patterns in the older individuals. Solid blue lines reflect MPS and the dashed red lines reflect MPB. Blue dashed areas reflect periods of positive net protein balance (NBAL) and red dotted areas reflect periods of negative NBAL. Adapted, with permission, from Oikawa SY, et al., 2019 200.


Figure 7. Schematic representation of the factors that contribute to the development of anabolic resistance of protein synthesis with aging.


Figure 8. Resistance exercise is a potent stressor that activates numerous signaling cascades within skeletal muscle. However, many of these signaling events are generic features of exercise, and so are also seen with aerobic training. Recent evidence has shown that exercise‐induced changes in mitochondrial, extracellular matrix (ECM), and angiogenesis‐related gene expression play an important role in muscle growth with resistance exercise training. Importantly, rather than functioning in isolation, these genes are members of hierarchical networks that interact to bring about changes in phenotype (i.e., muscle hypertrophy). These interactions are difficult to model using low‐throughput analytical techniques. The figure shows two trajectories: higher responders and lower responders. Higher responders activate the genes shown in the gears, which leads to muscle hypertrophy. Lower responders have some sort of block (represented in the figure as a crowbar preventing the gears from turning), perhaps inflammation, that may prevent sufficient activation of these gene networks, leading to negligible hypertrophy.


Figure 9. Muscle disuse is associated with an early reduction in mitochondrial transcripts and protein abundance that precedes and may drive, alterations in gene expression related to protein metabolism (i.e., synthesis and breakdown‐related genes/proteins). Solid black arrows depict known relationships, whereas dotted blue arrows depict hypothetical relationships based predominantly on evidence from preclinical models.
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Article Title: Resistance Exercise, Aging, Disuse, and Muscle Protein Metabolism
 

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James McKendry, Tanner Stokes, Jonathan C. Mcleod, Stuart M. Phillips. Resistance Exercise, Aging, Disuse, and Muscle Protein Metabolism. Compr Physiol 2021, 11: 2249-2278. doi: 10.1002/cphy.c200029