Respiratory muscle plasticity

Abstract

Muscle plasticity is defined as the ability of a given muscle to alter its structural and functional properties in accordance with the environmental conditions imposed on it. As such, respiratory muscle is in a constant state of remodeling, and the basis of muscle's plasticity is its ability to change protein expression and resultant protein balance in response to varying environmental conditions. Here, we will describe the changes of respiratory muscle imposed by extrinsic changes in mechanical load, activity, and innervation. Although there is a large body of literature on the structural and functional plasticity of respiratory muscles, we are only beginning to understand the molecular-scale protein changes that contribute to protein balance. We will give an overview of key mechanisms regulating protein synthesis and protein degradation, as well as the complex interactions between them. We suggest future application of a systems biology approach that would develop a mathematical model of protein balance and greatly improve treatments in a variety of clinical settings related to maintaining both muscle mass and optimal contractile function of respiratory muscles.

Figure 1

Transmission electron micrograph of a skeletal muscle sarcomere. The Z-disc defines the boundary of the sarcomere. The striations are formed by the highly organized arrangement of thick and thin filaments. Scale bar represents 500 nm.

Figure 2

Four different types of motor units - slow-twitch, fatigue resistant (type S), fast-twitch, fatigue resistant (type FR), fast-twitch, fatigue intermediate (type FInt), and fast-twitch, fatigable (type FF) - are classified based on contractile and fatigue properties of innervated muscle fibers (MyHC_Slow, MyHC_2A, MyHC_2X, and MyHC_2B). The speed of contraction varies between the motor units. Modified from Mantilla and Sieck (148), with permission.

Figure 3

Motor unit recruitment model in the rat diaphragm muscle during ventilatory and non-ventilatory behaviors, based on a model developed previously in cats and hamsters by Sieck and Fournier (239, 240). Motor units are recruited in a specific order (type S → type FR → type FInt → type FF) to accomplish the required forces. From Mantilla et al. (147), with permission.

Figure 4

Comparison of experimental models (SH, DNV, and TTX) for the study of activity-induced diaphragm muscle plasticity. Adapted from Mantilla and Sieck (148), with permission.

Figure 5

Cross-sectional area (CSA) adaptations to 14 days of inactivity induced by spinal hemisection (SH), unilateral denervation (DNV), or tetrodotoxin nerve block (TTX), among fibers expressing different MyHC isoforms. Mean and SE of the fiber CSA are plotted according to fiber type. * Significantly different from the control group (p < 0.05 for all comparisons). Adapted from Miyata et al. (161), with permission.

Figure 6

DNV-induced change in rat diaphragm muscle net protein balance as determined by performing parallel but separate incubations of strips from the same diaphragm muscle for protein synthesis and protein degradation measurements. Mean and SE of the percent change relative to sham controls are plotted over time after DNV. * Significantly different from the sham control group at the same DNV time-point, † Significantly different from 1 and 3 days after DNV, # Significantly different from 5 days after DNV (p < 0.05 for all comparisons). Figure from Argadine et al. (3), with permission.

Figure 7

Simplified model of signaling pathways regulating protein synthesis and degradation. Arrows denote activating events, whereas perpendicular lines denote inhibitory events. The solid lines indicate direct activation. The dashed lines indicate indirect activation, whereby intermediate steps are involved but are not specified in this schematic. Protein synthesis is regulated by protein kinase B (Akt), p44/42 MAPK (ERK) and AMP-activated protein kinase (AMPK), resulting in activation of the downstream targets mammalian target of rapamycin (mTOR), glycogen synthase kinase-3β (GSK3β), MAPK-interacting kinases 1/2 (MNK1/2), p70S6 kinase (p70S6K), eIF4E-binding protein 1 (4EBP1), and eukaryotic initiation factors 2B and 4E (eIF2B and eIF4E). Conversely, Akt is responsible for the phosphorylation status of forkhead box protein (FoxO). Upon phosphorylation by Akt, FoxO leaves the nucleus and becomes inactive, thus preventing protein degradation. If Akt activity is suppressed, FoxO becomes dephosphorylated, translocates to the nucleus, and exerts its transcriptional effects on atrogenes to induce protein degradation through the ubiquitin-proteasome pathway. Figure from Argadine et al. (4), with permission.

Figure 8

Steps in a systems biology approach. The first two steps use data to identify components and interactions in order to generate a reconstruction. The last steps generate a mathematical model to predict network behavior.