Signaling pathways controlling skeletal muscle mass

Abstract

The molecular mechanisms underlying skeletal muscle maintenance involve interplay between multiple signaling pathways. Under normal physiological conditions, a network of interconnected signals serves to control and coordinate hypertrophic and atrophic messages, culminating in a delicate balance between muscle protein synthesis and proteolysis. Loss of skeletal muscle mass, termed "atrophy", is a diagnostic feature of cachexia seen in settings of cancer, heart disease, chronic obstructive pulmonary disease, kidney disease, and burns. Cachexia increases the likelihood of death from these already serious diseases. Recent studies have further defined the pathways leading to gain and loss of skeletal muscle as well as the signaling events that induce differentiation and post-injury regeneration, which are also essential for the maintenance of skeletal muscle mass. In this review, we summarize and discuss the relevant recent literature demonstrating these previously undiscovered mediators governing anabolism and catabolism of skeletal muscle.

Figure 1.

The signaling pathways involved in the control of skeletal muscle atrophy and hypertrophy. Signaling activated by insulin-like growth factor-1 (IGF1) positively regulates muscle mass, primarily via induction of protein synthesis, downstream of Akt and mTOR. The myostatin/GDF11/activin pathway negatively regulates muscle size, as a result of the phosphorylation of SMAD2/3 – primarily by inhibiting Akt. IGF1 acts via the IGF receptor (IGFR), and the insulin receptor substrate 1 (IRS1), – activating Akt. Akt activates mTOR complex 1 (mTORC1). mTORC1 is a multiprotein complex that requires the protein raptor for its function and is acutely inhibited by FKBP/rapamycin. mTORC1 controls protein synthesis by phosphorylating S6 kinase 1 (S6K) and eIF4E-binding protein (4E-BP). The multiprotein complex mTORC2 includes the protein rictor and contributes to the activation of Akt. Downstream targets of Akt include glycogen synthase kinase 3β (GSK3β) and Forkhead box O (FOXO) transcription factors. Inhibition of GSK3β by Akt relieves inhibition onto the initiation factor eIF2B, and thereby increases protein synthesis. Activation of Akt also inhibits FOXO and decreases expression of the E3 ubiquitin ligases Muscle Atrophy Fbox (MAFbx) and Muscle Ring Finger1 (MuRF1). Substrates of MAFbx and MuRF1 are the initiation factor eIF3-f and myosin chains, respectively. Another more recently discovered E3 ligase is Fbxo40, which can ubiquitinate IRS1 upon IGF1 stimulation, short-circuiting this pathway unless the muscle is capable of synthesizing new IGF1, via maintenance of TORC1/protein synthesis signaling. To induce hypertrophy, in addition to the classical IGF-1/Akt pathway, more recently the Galpha-i2 pathway has been shown to induce hypertrophy via PKC, bypassing Akt. In addition to the PKC pathway downstream of Galpha-i2, there is a PKC-independent pathway which involves inhibition of HDAC4.The myostatin/TGFβ pathway acts via several receptors and results in the activation of Smad 2,3. Activation of Smad proteins inhibits the function of Akt and the expression of MAFbx and MuRF1 by FOXO transcription factors. The function of Smad 2,3 is also inhibited by mTORC1. (see colour version of this figure at www.informahealthcare.com/bmg).