Mechanisms of muscle atrophy and hypertrophy: implications in health and disease

Abstract

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.

Fig. 1. Insulin and IGF1 bind to specific receptors (IR, IGF1R) that activate a cascade of phosphorylation events resulting in enhancement of protein synthesis and inhibition of protein breakdown.

Upon receptor activation, IRS1 promotes phosphatidylinositol-3,4,5 triphosphates (PIP3,4,5) generation on the plasma membrane by recruiting the kinase PI3K. Plakoglobin helps the PI3K association to IR. The lipid signal on the plasma membrane promotes AKT recruitment and activation operated by PDK1 and mTORC2 complex. Then AKT positively or negatively modulates a plethora of targets including the mTORC1 complex for protein synthesis, ACL for ATP production, and FoxO for protein degradation. mTORC1 complex is another hub that affects many different biological processes, including autophagy. In fact, mTORC1 phosphorylates and inhibits ULK1. The pathway has several feedbacks that modulate its activity. For instance, activation of mTORC1 blocks IRS1 via S6K1 and consequently, inhibits AKT. AMPK, whose activity is increased by energy stress, is another important modulator of the pathway because blocks mTORC1 and activate FoxO and the autophagy system. Dotted lines depict pathways whose molecular mechanisms and role in adult skeletal muscle have yet to be completely defined.

Fig. 2. TGFβ superfamily activates two different pools of transcription factors with the opposite function.

Myostatin (GDF8), activinA/B, TGFβ, and GDF11 bind to type II receptors like ActRIIB/IIA that activate type I receptors (ALK4/5/7), which phosphorylate and induce Smad2/3 to form a complex with Smad4 and translocate into the nucleus. BMP ligands bind BMP type II receptors like BMPRII but also ActRIIB/A and recruit type 1 receptors such as ALK2/3/6 to phosphorylate and activate Smad 1/5/8 that form a complex with Smad4. The BMP and TGFβ/myostatin/activins ligands are modulated extracellularly by the inhibitory action of cytokines, such as noggin and follistatin. Another level of regulation happens in the cytosol where Smad6 and 7 negatively modulate the BMP and myostatin/activin pathway. Finally, both Smad2/3 and Smad1/5/8 transcription factors regulate mTOR activity, but the underlying mechanism are unclear. Dotted lines depict pathways whose molecular mechanisms and role in adult skeletal muscles have yet to be completely defined.

Fig. 3. Autophagosome formation is highly regulated and involves many proteins.

Assembly of the ULK1-FIP200-Atg13-Atg101 complex primes the induction of Beclin1-VPS34-VPS15 complex to generate phosphatidylinositol-3-phosphate (PIP3) lipids in membranes of different organelles (e.g., endoplasmic reticulum). The ULK1 and the Beclin1 complexes are negatively or positively modulated by mTOR and AMPK, respectively. The PIP3 signal recruits the conjugation systems (LC3/GABARAP and Atg5/Atg12/Atg16) of autophagy that induces the covalent linking of phospholipids with LC3-GABARAP proteins for membrane’s commitment to becoming autophagosomes. Then the committed membrane (phagophore assembly site or isolation membrane) elongates and closes to form a double-layered vesicle (autophagosome) that is docked to the lysosome (Ly) for cargo destruction. The endoplasmic reticulum site where autophagosomes are formed, which is revealed by DFCP1 protein, is named omegasome.

Fig. 4. Soluble TNFα binds, induces trimerization, and activates TNF-receptor (TNFR) which recruits several adaptor proteins (e.g., TRAF2) that trigger IKK complex activation.

IKK phosphorylates the inhibitory of NF-kB, named IkB, that undergoes proteasomal-dependent degradation leading to NF-kB release and nuclear translocation. IKK activation leads also to inhibition of the insulin pathway by blocking IRS1. Tweak, another member of TNF family, binds to the receptor, named Fn14, which upon activation recruits proteins such as TRAF6 to induce NF-kB as well as FoxO activation.

Fig. 5. Scheme of the principal pathways induced by the interstitial cells or by cancer that control protein degradation and muscle atrophy.

Cancer growth induces hyperproliferation of Pax7-positive muscle stem cells, named satellite cells (SC), that do not fuse with myofiber and triggers an atrophy program whose insights are still unclear. When exposed to an increased TGFβ signaling, satellite cells express Twist that induces myostatin expression and secretion. The release of myostatin causes a second wave in myofibers where Twist and Smad3 cooperate to promote muscle atrophy. Denervation, cause expansion of the fibro-adipogenic precursor (FAP) cells which induce an inflammatory response via IL6 leading to Stat3 activation in muscle and induction of an atrophy program. Cancer derived exosomes deliver HSP70/90 to myofibers that activate TLR4 and an atrophy program. Dotted lines depict pathways whose molecular mechanisms and role in adult skeletal muscle have yet to be completely defined.