Cellular and Molecular Mechanisms of Chronic Inflammation in Aging of Skeletal Muscle

Aging of skeletal muscle is typically accompanied by declining regenerative potential, due in part to alternations in the resident muscle stem cell population, known as satellite cells. Previous data suggest that highly regenerative satellite cells in young mice are damaged by aging and chronic inflammation, driven in part by the transcription factor NF-κB. Interestingly, myogenic function of aged satellite cells can be restored by exposure to blood-borne factors from young mice, in association with decreased expression of many of pro-inflammatory genes. These observations led me to hypothesize that strategies counteracting the chronic inflammatory state in muscle might improve regenerative function in old age through enhancement of satellite cell function. To test this hypothesis, this study aims to define the molecular factors that promote chronic muscle inflammation with aging, evaluate their impact on satellite cell functions, and determine whether inhibition of the inflammatory process indeed reverses age-related muscle dysfunction. Utilization of well-established mouse models reveals that NF-κB activity has a detrimental effect on satellite cell function via non-cell-autonomous mechanisms, and that inhibition of NF-κB activity and its downstream target phospholipase A2 in skeletal muscle fibers preserves muscle regenerative potential in aged animals. In addition, this study reports the restrictive role of IL-6, a pro-inflammatory cytokine widely recognized as a biomarker of chronic inflammation, on the myogenic function of satellite cells. Finally, this study shows that systemic inhibition of inflammation using the NF-κB antagonist sodium salicylate decreases inflammatory gene expression, including IL-6, in aged muscle and improves muscle regeneration after injury. Thus, chronic inflammation in muscle, in association with elevated NF-κB activity and its downstream pro-inflammatory factors, impairs muscle regeneration by extrinsically limiting the myogenic function of satellite cells in aged animals. Importantly, such impairment was shown to be reversible by reducing the inflammatory tone both at tissue and systemic level. By discovering the molecular mediators NF-κB signaling in muscle, this study provides potential therapeutic avenues for elderly patients with declining muscle mass and function.Medical Science

Photothermal Polymer Nanocomposites of Tungsten Bronze Nanorods with Enhanced Tensile Elongation at Low Filler Contents

We present polymer nanocomposites of tungsten bronze nanorods (TBNRs) and ethylene propylene diene monomers (EPDM). The combination of these components allows the simultaneous enhancement in the mechanical and photothermal properties of the composites at low filler contents. The as-synthesized TBNRs had lengths and diameters of 14.0 +/- 2.4 nm and 2.5 +/- 0.5 nm, respectively, and were capped with oleylamine, which has a chemical structure similar to EPDM, making the TBNRs compatible with the bulk EPDM matrix. The TBNRs absorb a wide range of near-infrared light because of the sub-band transitions induced by alkali metal doping. Thus, the nanocomposites of TBNRs in EPDM showed enhanced photothermal properties owing to the light absorption and subsequent heat emission by the TBNRs. Noticeably, the nanocomposite with only 3 wt% TBNRs presented significantly enhanced tensile strain at break, in comparison with those of pristine EPDM, nanocomposites with 1 and 2 wt % TBNRs, and those with tungsten bronze nanoparticles, because of the alignment of the nanorods during tensile elongation. The photothermal and mechanical properties of these nanocomposites make them promising materials for various applications such as in fibers, foams, clothes with cold weather resistance, patches or mask-like films for efficient transdermal delivery upon heat generation, and photoresponsive surfaces for droplet transport by the thermocapillary effect in microfluidic devices and microengines

The Grind for Good Data: Understanding ML Practitioners' Struggles and Aspirations in Making Good Data

We thought data to be simply given, but reality tells otherwise; it is costly, situation-dependent, and muddled with dilemmas, constantly requiring human intervention. The ML community's focus on quality data is increasing in the same vein, as good data is vital for successful ML systems. Nonetheless, few works have investigated the dataset builders and the specifics of what they do and struggle to make good data. In this study, through semi-structured interviews with 19 ML experts, we present what humans actually do and consider in each step of the data construction pipeline. We further organize their struggles under three themes: 1) trade-offs from real-world constraints; 2) harmonizing assorted data workers for consistency; 3) the necessity of human intuition and tacit knowledge for processing data. Finally, we discuss why such struggles are inevitable for good data and what practitioners aspire, toward providing systematic support for data works

miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition

Hyperglycemia-induced stress in the brain of patients with diabetes triggers the disruption of blood-brain barrier (BBB), leading to diverse neurological diseases including stroke and dementia. Recently, the role of microRNA becomes an interest in the research for deciphering the mechanism of brain endothelial cell damage under hyperglycemia. Therefore, we investigated whether mircoRNA Let7A (miR-Let7A) controls the damage of brain endothelial (bEnd.3) cells against high glucose condition. Cell viability, cell death marker expressions (p-53, Bax, and cleaved poly ADP-ribose polymerase), the loss of tight junction proteins (ZO-1 and claudin-5), proinflammatory response (interleukin-6, tumor necrosis factor-α), inducible nitric oxide synthase, and nitrite production were confirmed using MTT, reverse transcription-PCR, quantitative-PCR, Western blotting, immunofluorescence, and Griess reagent assay. miR-Let7A overexpression significantly prevented cell death and loss of tight junction proteins and attenuated proinflammatory response and nitrite production in the bEnd.3 cells under high glucose condition. Taken together, we suggest that miR-Let7A may attenuate brain endothelial cell damage by controlling cell death signaling, loss of tight junction proteins, and proinflammatory response against high glucose stress. In the future, the manipulation of miR-Let7A may be a novel solution in controlling BBB disruption which leads to the central nervous system diseases

Mst1-FoxO Signaling Protects Naïve T Lymphocytes from Cellular Oxidative Stress in Mice

Background: The Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in Drosophila. InC. elegans, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, Mst1, plays a role in apoptosis induced by various types of apoptotic stress. Mst1 also regulates peripheral naïve T cell trafficking and proliferation in mice. However, its functions in mammals are not fully understood. Methodology/Principal Findings: Here, we report that the Mst1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naïve T cells. In Mst1 2/2 mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in Mst1 2/2 T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored Mst1 2/2 T cell survival. Crossing Mst1 transgenic mice (Mst1 Tg) with Mst1 2/2 mice reduced ROS levels and restored normal numbers of peripheral naïve T cells in Mst1 Tg;Mst1 2/2 progeny. Interestingly, peripheral T cells from Mst1 2/2 mice were hypersensitive to c-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant. Conclusions/Significance: These data support the hypothesis that tolerance to increased levels of intracellular RO

Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusion in vivo and the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditions in vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death

Phosphorylation of Histone H2A.X in Peripheral Blood Mononuclear Cells May Be a Useful Marker for Monitoring Cardiometabolic Risk in Nondiabetic Individuals

Phosphorylation of H2A.X (serine 139) in the histone H2A family located in the downstream of the DNA damage kinase signaling cascade is an important indicator of DNA damage. Recently, phosphorylation of H2A.X was proposed as a sensitive biomarker of aging. This study investigated if phosphorylation of H2A.X in peripheral blood mononuclear cells (PBMCs) is associated with cardiometabolic risk in nondiabetic individuals. Basic parameters and oxidative stress/inflammatory markers were measured in nondiabetic healthy Koreans (n = 119). Phosphorylation of H2A.X was measured randomly among the study subjects using a flow cytometer. According to the number of metabolic syndrome risk factor (MetS-RF), the study subjects were subdivided into "super healthy" (MetS − RF = 0, n = 71) and "MetS-risk" (MetS − RF ≥ 1, n = 48) groups. Phosphorylation of H2A.X in PBMCs (percentages and mean fluorescence intensity) was significantly higher in the MetS-risk group than in the super healthy group after adjusting for age, sex, cigarette smoking, and alcohol consumption. Phosphorylated H2A.X was positively correlated with the number of MetS-RF as well as waist circumference, blood pressures, triglyceride, Hb A1C , oxidized LDL, high sensitivity C-reactive protein, tumor necrosis factor-alpha, and alanine aminotransferase after the adjustment. The present study suggested that phosphorylated H2A.X in circulating PBMCs measured by flow cytometer may be a useful marker for monitoring cardiometabolic risk in nondiabetic individuals

Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function

Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-κB activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-κB signaling in muscle satellite cells or myofibers on recovery after damage. These studies reveal that NF-κB activity in differentiated myofibers is sufficient to drive dysfunction of muscle regenerative cells via cell-non-autonomous mechanisms. Inhibition of NF-κB, or its downstream target Phospholipase A2, in myofibers rescued muscle regenerative potential in aged muscle. Moreover, systemic administration of sodium salicylate, an FDA-approved NF-κB inhibitor, decreased inflammatory gene expression and improved repair in aged muscle. Together, these studies identify a unique NF-κB regulated, non-cell autonomous mechanism by which stem cell function is linked to lipid signaling and homeostasis, and provide important new targets to stimulate muscle repair in aged individuals

Structural basis for potency differences between GDF8 and GDF11.

BACKGROUND: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. RESULTS: Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. CONCLUSIONS: These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined