Signaling Pathways That Control Muscle Mass

Abstract

The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue's remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research.

Keywords: atrophy; hypertrophy; sarcopenia; skeletal muscle.

Figure 1

Pathways involved in protein synthesis. During muscle hypertrophy, the binding of insulin-like growth factor 1 (IGF-1)/insulin to their respective receptors activates IRS–PI3K–Akt–mTORC1 signaling, which is further stimulated by the presence of amino acids. The mTORC1 complex then enhances protein synthesis by inhibiting the eukaryotic translation initiator factor 4E (eIF4E) inhibitor 4E-binding protein 1 (4E-BP1) and activating p70S6K-S6-mediated protein translation. mTOR also blocks proteolysis by inhibiting autophagy initiation factors Unc-51 like autophagy activating kinase (ULK) 1/2. Clenbuterol and formoterol promote hypertrophy by binding to the adrenergic receptor and activating adenylate cyclase (AC)-PKA signaling, which culminates in the activation of Akt-mTOR. In addition to enhancing protein synthesis, Akt also blocks proteolysis by phosphorylating and inhibiting members of the forkhead box O family of transcription factors (FoxO), as well as activating glycogen synthase kinase (GSK) 3 and ATP citrate lyase (ACL). Fibroblast growth factor (FGF)19 enhances protein synthesis by binding to the βKlotho receptor and stimulating the extracellular signal-regulated kinase (ERK), which directly contributes to protein synthesis. Moreover, the binding of bone morphogenetic protein (BMP)7/13/14 to the BMPR receptor promotes muscle growth through the formation of a SMAD1/5/8–SMAD4 complex, which activates a hypertrophic transcriptional program. Calcium signaling also contributes to hypertrophy through the activation of calmodulin (CaM)-dependent kinase (CaMK) and phosphatase calcineurin, which stimulates the pro-growth transcription factor nuclear factor of activated T-cell (NFAT). Increased availability of nutrients and energy in the form of ATP further contribute to the auspicious environment that is permissive for muscle growth. Green shapes indicate positive regulators of muscle mass, whereas red shapes indicate negative regulators.

Figure 2

Pathways involved in protein degradation. During muscle atrophy, decreased binding of IGF-1/insulin to their respective receptors and/or increased binding of glucocorticoids to the glucocorticoid receptor (GR) result in reduced Akt/mTOR activation. This leads to diminished protein synthesis mediated by 4E-BP1-induced inhibition of eIF4E. Diminished mTOR activity also leads to the stimulation of autophagy through ULK1/2 signaling. At the same time, reduced Akt activity results in the release of FoxO from its cytosolic captivity, allowing it to activate an atrophic program by stimulating the expression of atrogenes belonging to the autophagy lysosome and ubiquitin proteasome proteolytic pathways. This sustains the increased proteolytic activity of these systems. The FoxO-induced atrophic program can be further enhanced by Dickkopf 3 (Dkk3) and blocked by PGC-1α and Foxk. Increased binding of activins (ActivinA, growth and differentiation factor 11 (GDF11)) and myostatin to the Activin type 2 (ActRIIB) receptor can contribute to atrophy through the activation of activin receptor-like kinase (ALK)2/3 and the formation of the SMAD2/3-SMAD4 complex, which in addition to further inhibiting Akt, also induces the expression of proteins involved in atrophy. Muscle atrophy is often accompanied by inflammation, which contributes to proteolysis. Increased levels of circulating cytokines such as tumor necrosis factor α (TNFα), TNF-like weak inducer of apoptosis (TWEAK), and IL6 leads to the activation of TRAF6, TRADD, IKK, and JAK which, in turn, activate NF-κB, Stat3, and FoxO, thus enhancing the expression of atrogenes. Mitochondrial dysfunction is also often observed during muscle atrophy, which leads to increased oxidative stress and mitophagy. Oxidative stress stimulates the release of IGF21, which then feeds back onto muscle, enhancing the expression of mitophagy receptor Bnip3. Accumulation of PINK1 and localization of E3 ubiquitin ligase Parkin as well as Bnip3 on the mitochondrial membrane lead to the elimination of dysfunctional mitochondria by mitophagy. Muscle atrophy is also associated with ER stress, which activates the unfolded protein response (UPR). UPR-activated IRE and PERK-eIF2α then promote atrophic transcriptional programs regulated by X-box binding protein 1 (XBP1) and ATF4, respectively. HDAC4, which is normally supressed by CaMK, is upregulated during denervation, resulting in the inhibition of Dach2, a transcriptional repressor of myogenin. This culminates in increased myogenin-mediated transcription of synaptic factors MuSK and AChR, as well as atrogenes muscle ring finger1 (MuRF1) and Atrogin-1. Green shapes indicate positive regulators of muscle mass, whereas red shapes indicate negative regulators.