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.
Metal halide perovskite crystal structures have emerged as a class of optoelectronic materials, which combine the ease of solution processability with excellent optical absorption and emission ...qualities. Restricting the physical dimensions of the perovskite crystallites to a few nanometers can also unlock spatial confinement effects, which allow large spectral tunability and high luminescence quantum yields at low excitation densities. However, the most promising perovskite structures rely on lead as a cationic species, thereby hindering commercial application. The replacement of lead with nontoxic alternatives such as tin has been demonstrated in bulk films, but not in spatially confined nanocrystals. Here, we synthesize CsSnX3 (X = Cl, Cl0.5Br0.5, Br, Br0.5I0.5, I) perovskite nanocrystals and provide evidence of their spectral tunability through both quantum confinement effects and control of the anionic composition. We show that luminescence from Sn-based perovskite nanocrystals occurs on pico- to nanosecond time scales via two spectrally distinct radiative decay processes, which we assign to band-to-band emission and radiative recombination at shallow intrinsic defect sites.
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.”
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.
Influenza is a viral infection that primarily spreads via fluid droplets from an infected person's coughs and sneezes to others nearby. Social contact networks and the way people interact within them ...are thus important to its spread. We developed a method to characterize the social contact network for the potential transmission of influenza and then applied the method to school aged children and teenagers.
Surveys were administered to students in an elementary, middle and high-school in the United States. The social contact network of a person was conceptualized as a set of groups to which they belong (e.g., households, classes, clubs) each composed of a sub-network of primary links representing the individuals within each group that they contact. The size of the group, number of primary links, time spent in the group, and level of contact along each primary link (near, talking, touching, or kissing) were characterized. Public activities done by groups venturing into the community where random contacts occur (e.g., friends viewing a movie) also were characterized.
Students, groups and public activities were highly heterogeneous. Groups with high potential for the transmission of influenza were households, school classes, friends, and sports; households decreased and friends and sports increased in importance with grade level. Individual public activity events (such as dances) were also important but lost their importance when averaged over time. Random contacts, primarily in school passing periods, were numerous but had much lower transmission potential compared to those with primary links within groups. Students are highly assortative, interacting mainly within age class. A small number of individual students are identified as likely "super-spreaders".
High-school students may form the local transmission backbone of the next pandemic. Closing schools and keeping students at home during a pandemic would remove the transmission potential within these ages and could be effective at thwarting its spread within a community. Social contact networks characterized as groups and public activities with the time, level of contact and primary links within each, yields a comprehensive view, which if extended to all ages, would allow design of effective community containment for pandemic influenza.
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.
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.
GDF11 is a secreted factor in the TGFß family of cytokines. Its nearest neighbor evolutionarily is myostatin, a factor discovered as being a negative regulator of skeletal muscle growth. High profile ...studies several years ago suggested that GDF11 declines with age, and that restoration of systemic GDF11 to 'youthful' levels is beneficial for several age-related conditions. Particularly surprising was a report that supplementation of GDF11 aided skeletal muscle regeneration, as its homolog, myostatin, has the opposite role. Given this apparent contradiction in functionality, multiple independent labs sought to discern differences between the two factors and better elucidate age-related changes in circulating GDF11, with most failing to reproduce the initial finding of declining GDF11 levels, and, importantly, all subsequent studies examining the effects of GDF11 on skeletal muscle described an inhibitory effect on regeneration - and that higher doses induce skeletal muscle atrophy and cachexia. There have also been several studies examining the effect of GDF11 and/or the downstream ActRII pathway on cardiac function, along with several interesting reports on bone. A review of the GDF11 literature, as it relates in particular to aging and skeletal muscle, cardiac and bone biology, is presented.
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