Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance ...and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies.
Moiseeva and colleagues examined gene expression and chromatin (the DNA-protein complex in which genetic material is packaged in the nucleus) in the senescent cell populations from young and old ...animals. To explore the mechanism by which senescent cells block muscle regeneration, the group further profiled gene expression in the cells, and found a decrease in expression of genes related to the function of energy-producing organelles called mitochondria, and an increase in inflammatory genes, among other changes. In particular, interferon-stimulated genes (which are associated with inflammation) are upregulated in both ageing and senescence. ...the authors found changes in collagen production, which have previously been linked to fibrosis6.
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.
Activation of the PI3 kinase pathway can induce skeletal muscle hypertrophy, defined as an increase in skeletal muscle mass. In mammals, skeletal muscle hypertrophy occurs as a result of an increase ...in the size, as opposed to the number, of pre-existing skeletal muscle fibers. This pathway’s effects on skeletal muscle have been implicated most prominently downstream of Insulin-like growth factor 1 signaling. IGF-1’s pro-hypertrophy activity comes predominantly through its ability to activate the Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Akt is a serine-threonine protein kinase that can induce protein synthesis and block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1), by phosphorylating and thereby inhibiting the nuclear translocation of the FOXO (also called “forkhead”) family of transcription factors. Once phosphorylated by Akt, the FOXOs are excluded from the nucleus, and upregulation of MuRF1 and MAFbx is blocked. MuRF1 and MAFbx mediate atrophy by ubiquitinating particular protein substrates, causing them to undergo degradation by the proteasome. MuRF1’s substrates include several components of the sarcomeric thick filament, including Myosin Heavy Chain (MyHC). Thus, by blocking MuRF1 activation, IGF-1 helps prevent the breakdown of the thick filament under atrophy conditions.
IGF1/PI3K/Akt signaling also can dominantly inhibit the effects of a secreted protein called “myostatin,” which is a member of the TGFβ family of proteins. Deletion or inhibition of myostatin causes an increase in skeletal muscle size, because myostatin acts both to inhibit myoblast differentiation and to block the Akt pathway. Thus by blocking myostatin, PI3K/Akt activation stimulates differentiation and protein synthesis by this distinct mechanism. Myostatin induces the phosphorylation and activation of the transcription factors of Smad2 and Smad3, downstream of the ActRII (Activin Receptor type II)/Alk (Activin Receptor-like kinase) receptor complex. Other TGFβ-like molecules can also block differentiation, including TGF-b1, GDF-11, activinA, BMP-2 and BMP-7. As mentioned, myostatin also downregulates the Akt/mTOR/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using siRNA to RAPTOR, a component of “TORC1” (TOR signaling Complex 1), increases myostatin-induced phosphorylation of Smad2; this establishes a “feed-forward mechanism,” because myostatin can downregulates TORC1, and this downregulation in turn amplifies myostatin signaling. Blockade of RAPTOR also facilitates myostatin’s inhibition of muscle differentiation. When added to post-differentiated myotubes, myostatin causes a decrease in their diameter – however, this does not happen through the normal “atrophy pathway.” Rather than causing upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation, such as MyoD and myogenin. These findings show that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct “atrophy program.”
Increasing evidence suggests that long non-coding RNAs (LncRNAs) represent a new class of regulators of stem cells. However, the roles of LncRNAs in stem cell maintenance and myogenesis remain ...largely unexamined. For this study, hundreds of intergenic LncRNAs were identified that are expressed in myoblasts and regulated during differentiation. One of these LncRNAs, termed LncMyoD, is encoded next to the Myod gene and is directly activated by MyoD during myoblast differentiation. Knockdown of LncMyoD strongly inhibits terminal muscle differentiation, largely due to a failure to exit the cell cycle. LncMyoD directly binds to IGF2-mRNA-binding protein 2 (IMP2) and negatively regulates IMP2-mediated translation of proliferation genes such as N-Ras and c-Myc. While the RNA sequence of LncMyoD is not well conserved between human and mouse, its locus, gene structure, and function are preserved. The MyoD-LncMyoD-IMP2 pathway elucidates a mechanism as to how MyoD blocks proliferation to create a permissive state for differentiation.
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•LncMyoD is directly activated by MyoD during myogenesis•LncMyoD binds to IMPs and regulates mRNA translation•Human and mouse LncMyoD are functionally conserved despite low sequence homology
Long non-coding RNAs are regulators of various biological functions. Gong and Li et al. show that LncMyoD is a LncRNA target of MyoD during myogenesis and is required for myoblast differentiation by affecting IMP2-mediated mRNA translation. LncMyoD is functionally conserved between mouse and human, despite limited sequence homology.
To discuss the mechanisms of muscle loss during cachexia.
Cachexia can be defined as a wasting of lean body mass that cannot be reversed nutrionally, indicating a dysregulation in the pathways ...maintaining body composition. In skeletal muscle, during cachexia, there is an upregulation of protein degradation. A search for transcriptional markers of muscle atrophy led to the discovery of the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1). These genes are upregulated in multiple models of atrophy and cachexia. They target particular protein substrates for degradation via the ubiquitin/proteasome pathway. The insulin-like growth factor-1 can block the transcriptional upregulation of MuRF1 and MAFbx via the phosphatidylinositol-3 kinase/Akt/Foxo pathway. MuRF1's substrates include several components of the sarcomeric thick filament, including myosin heavy chain. Thus, by blocking MuRF1, insulin-like growth factor-1 prevents the breakdown of the thick filament, particularly myosin heavy chain, which is asymmetrically lost in settings of cortisol-linked skeletal muscle atrophy. Insulin-like growth factor-1/phosphatidylinositol-3 kinase/Akt signaling also dominantly inhibits the effects of myostatin, which is a member of the transforming growth factor-beta family of proteins. Deletion or inhibition of myostatin causes a significant increase in skeletal muscle size. Recently, myostatin has been shown to act both by inhibiting gene activation associated with differentiation, even when applied to postdifferentiated myotubes, and by blocking the phosphatidylinositol-3 kinase/Akt pathway.
These findings will help to define strategies to treat cachexia.
Skeletal muscle hypertrophy is defined as an increase in muscle mass, which in the adult animal comes as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle ...fibers. The protein growth factor insulin-like growth factor 1 (IGF-1) has been demonstrated to be sufficient to induce skeletal muscle hypertrophy. Over the past few years, signaling pathways which are activated by IGF-1, and which are responsible for regulating protein synthesis pathways, have been defined. More recently, it has been show that IGF-1 can also block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the ubiquitin-ligases MuRF1 and MAFbx (also called Atrogin-1). Further, it has been demonstrated recently that activation of the NF-κB transcription pathway, activated by cachectic factors such as TNFα, is sufficient to induce skeletal muscle atrophy, and this atrophy occurs in part via NF-κB-mediated upregulation of MuRF1. Further work has demonstrated a trigger for MAFbx expression upon treatment with TNFα—the p38 MAPK pathway. This review will focus on the recent progress in the understanding of molecular signalling, which governs skeletal muscle atrophy and hypertrophy, and the known instances of cross-regulation between the two systems.
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