Skeletal Muscle Recovery from Disuse Atrophy: Protein Turnover Signaling and Strategies for Accelerating Muscle Regrowth

Abstract

Skeletal muscle fibers have a unique capacity to adjust their metabolism and phenotype in response to alternations in mechanical loading. Indeed, chronic mechanical loading leads to an increase in skeletal muscle mass, while prolonged mechanical unloading results in a significant decrease in muscle mass (muscle atrophy). The maintenance of skeletal muscle mass is dependent on the balance between rates of muscle protein synthesis and breakdown. While molecular mechanisms regulating protein synthesis during mechanical unloading have been relatively well studied, signaling events implicated in protein turnover during skeletal muscle recovery from unloading are poorly defined. A better understanding of the molecular events that underpin muscle mass recovery following disuse-induced atrophy is of significant importance for both clinical and space medicine. This review focuses on the molecular mechanisms that may be involved in the activation of protein synthesis and subsequent restoration of muscle mass after a period of mechanical unloading. In addition, the efficiency of strategies proposed to improve muscle protein gain during recovery is also discussed.

Keywords: disuse atrophy; muscle regrowth; protein degradation; protein synthesis; recovery; reloading; skeletal muscle; unloading.

Figure 1

Simplified diagram showing the key regulatory factors involved in ribosome biogenesis. Arrows indicate stimulatory signals. mTORC1—mammalian/mechanistic target of rapamycin complex 1, c-Myc—c-myelocytomatosis oncogene, RNA Pol I, II or III—RNA polymerases I, II or III, rRNA—ribosomal RNA, tRNA—transfer RNA, RP—ribosomal proteins, 40S—small ribosomal subunit, 60S—large ribosomal subunit.

Figure 2

Simplified diagram depicting mechanoresponsive signaling pathways in skeletal muscle involved in the regulation of translational capacity and efficiency. Arrows indicate stimulatory signals, whereas T bars represent inhibitory signals. SAC—stretch-activated ion channels, FZD—frizzled protein (receptor), FAK—focal adhesion kinase, AKT—protein kinase B, TSC1/2—tuberous sclerosis complex1/2, DGKζ—zeta isoform of diacylglycerol kinase, PA—phosphatidic acid, mTORC1—mammalian/mechanistic target of rapamycin complex 1, p70S6K —ribosomal protein S6 kinase p70, 4E-BP1—eukaryotic initiation factor 4E binding protein, FOXO—forkhead box O protein, MuRF1—muscle RING finger, MAFbx—muscle atrophy F-box, c-Myc—c-myelocytomatosis oncogene, eIF3f—eukaryotic initiation factor 3f, GSK3β—glycogen synthase kinase-3β, LATS1/2—large tumor suppressor kinase 1/2, YAP—Yes-associated protein, TAZ—transcriptional coactivator with PDZ-binding motif.

Figure 3

Simplified diagram delineating key signaling pathways involved in skeletal muscle protein synthesis and degradation. Arrows indicate stimulatory signals, whereas T bars represent inhibitory signals. IGF-1—insulin-like growth factor 1, TNFα—tumor necrosis factor alpha, ERK1/2—extracellular signal-regulated kinase 1/2, IRS-1—insulin receptor substrate 1, AMPK—AMP-activated protein kinase, AKT—protein kinase B, TSC1/2—tuberous sclerosis complex1/2, NO—nitric oxide, nNOS—neuronal NO synthase, Trpv1—transient receptor potential cation channel subfamily V member 1, ROS—reactive oxygen species, REDD1—regulated in development and DNA damage response 1, mTORC1—mammalian/mechanistic target of rapamycin complex 1, p70S6K—ribosomal protein S6 kinase p70, 4E-BP1—eukaryotic initiation factor 4E binding protein, FOXO—forkhead box O protein, MuRF1—muscle RING finger, MAFbx—muscle atrophy F-box, c-Myc—c-myelocytomatosis oncogene, eIF3f—eukaryotic initiation factor 3f, GSK3β—glycogen synthase kinase 3β, eIF2B—eukaryotic initiation factor 2B, cGMP—cyclic guanosine monophosphate, eEF2K—eukaryotic elongation factor 2 kinase, eEF2—eukaryotic elongation factor 2, p90RSK—ribosomal protein S6 kinase p90, ULK1—unc-51-like autophagy activating kinase, LC3—microtubule-associated proteins 1A/1B light chain 3B, NF-κB—nuclear factor κB.

Figure 4

Schematic illustration of the effects of possible therapeutic interventions on the anabolic pathways in reloaded skeletal muscle. Arrows indicate stimulatory signals. β2-AR—beta 2 adrenoreceptor, PKA—protein kinase 2, mTORC1—mammalian/mechanistic target of rapamycin complex 1, p70S6K—ribosomal protein S6 kinase p70, rpS6—ribosomal protein S6, FAK—focal adhesion kinase, Epac—exchange protein directly activated by cyclic AMP, ERK—extracellular signal-regulated kinase, AKT—protein kinase B, CCL—cyclic compressive loading, HMB—beta-hydroxy-beta-methyl butyrate, EAA—essential amino acids, NMES—neuromuscular electrical stimulation, MENS—microcurrent electrical nerve stimulation, E80—polyphenol-rich fraction of black tea, NP—nucleoprotein (a combination of amino acids and nucleotides).