Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. We used Cre-LoxP methodology to generate mice with germline [muscle creatine kinase promoter (P-MCK and C-MCK)] or inducible [tamoxifen-activated, human skeletal actin promoter (P-iHSA and C-iHSA)] knockout of p300 or CBP. A subset of P-MCK and C-MCK mice were switched to a calorie-restriction diet (60% of ad libitum intake) or high-fat diet at 10 wk of age. For P-iHSA and C-iHSA mice, knockout was induced at 10 wk of age. At 13–15 wk of age, we measured whole-body energy expenditure, oral glucose tolerance, and/or ex vivo skeletal muscle insulin sensitivity. Although p300 and CBP protein abundance and mRNA expression were reduced 55%–90% in p300 and CBP knockout mice, there were no genotype differences in energy expenditure or fasting glucose and insulin concentrations. Moreover, neither loss of p300 or CBP impacted oral glucose tolerance or skeletal muscle insulin sensitivity, nor did their loss impact alterations in these parameters in response to a calorie restriction or high-fat diet. Muscle-specific loss of either p300 or CBP, be it germline or in adulthood, does not impact energy expenditure, glucose tolerance, or skeletal muscle insulin action.

While obesity and insulin resistance are known risk factors for wound complications after total joint arthroplasty (TJA), the biologic causes remain to be elucidated. Recently, neutrophil extracellular trap formation (NETosis) was identified as a mediator of delayed wound healing in insulin resistant states. Herein, we explored the relationship between obesity, insulin resistance and biomarkers of NET formation in TJA subjects. We enrolled 14 obese (body mass index [BMI]≥30 kg/m2), and 15 lean (BMI<30 kg/m2) subjects undergoing primary knee or hip TJA. On the day of surgery, skeletal muscle proximal to the operated joint and plasma were collected. Protein abundance of NETosis biomarkers, peptidylarginine deaminase 4 (PAD4) and neutrophil elastase (NE) were assessed in skeletal muscle by immunoblotting and metabolic parameters (glucose, insulin, triglycerides, free fatty acids) and cell-free double-stranded DNA (cf-dsDNA) were assessed in plasma and were correlated with obesity and insulin resistance (as measured by the homeostatic model assessment for insulin resistance). When comparing lean and obese subjects, there were no significant differences in plasma cf-dsDNA or skeletal muscle NE or PAD4 abundance. In contrast, skeletal muscle PAD4 abundance, but not NE or plasma cf-dsDNA, was positively correlated with insulin resistance. Compared to insulin sensitive subjects, insulin resistant TJA subjects have higher expression of PAD4 at the surgical site and therefore may have higher rates of NET formation, which may lead to delayed surgical site wound healing.

Tixagevimab and cilgavimab treatment was associated with higher rates of cardiovascular events in a post-hoc analysis of a phase 3 trial. In this large population-based propensity-matched study, we found no increased risk of cardiovascular events up to 90 days after tixagevimab and cilgavimab administration, including in patients with pre-existing cardiovascular disease.

Whether the histone deacetylase (HDAC) and sirtuin families of protein deacetylases regulate insulin-stimulated glucose uptake, independent of their transcriptional effects, has not been studied. Our objective was to determine the nontranscriptional role of HDACs and sirtuins in regulation of skeletal muscle insulin action. Basal and insulin-stimulated glucose uptake and signaling and acetylation were assessed in L6 myotubes and skeletal muscle from C57BL/6J mice that were treated acutely (1 h) with HDAC (trichostatin A, panobinostat, TMP195) and sirtuin inhibitors (nicotinamide). Treatment of L6 myotubes with HDAC inhibitors or skeletal muscle with a combination of HDAC and sirtuin inhibitors increased tubulin and pan-protein acetylation, demonstrating effective impairment of HDAC and sirtuin deacetylase activities. Despite this, neither basal nor insulin-stimulated glucose uptake or insulin signaling was impacted. Acute reduction of the deacetylase activity of HDACs and/or sirtuins does not impact insulin action in skeletal muscle.

Introduction: Individuals with antibodies to citrullinated protein antigens (ACPA) have higher risk for cardiovascular disease (CVD). Cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα), have been identified as pro-atherogenic. While the association between ACPA and cytokines has been studied in rheumatoid diseases, it has not been studied in the general population. We hypothesized that ACPA are positively associated with IL-6, c-reactive protein (CRP), and TNFα; and that gender and race/ethnicity modify this association. Methods: In 1743 Multi-Ethnic Study of Atherosclerosis participants without clinical CVD, we evaluated the association between number of ACPA and IL-6, CRP, and TNFα using multivariable linear regression. We adjusted for demographics, CVD risk factors, and medication use; and tested for interactions by gender and race/ethnicity. ACPA was measured as an array of 38 individual ACPA with the cut-off for positivity for each antibody set at the 95 th percentile. CRP, IL-6, and TNFα were measured in serum of fasting participants; values were log-transformed to reduce skewness. Results: Average age was 64.7±9.7 years; 50% were women, 40% Caucasian, 13% Chinese American, 21% African American, and 26% Hispanic American. Approximately 31% (537) had at least one positive ACPA. In the fully adjusted analysis, each additional ACPA was associated with 0.3±0.1% (p=0.005) higher serum IL-6 and 0.6±0.2% (p=0.007) higher CRP. ACPA was not associated with TNFα. Associations of ACPA with CRP were modified by gender (p interaction = 0.000) and race/ethnicity (p interaction = 0.000). In men, each additional ACPA was associated with 0.4±0.1% (p=0.015) higher IL-6 and 0.7±0.2% (p=0.007) higher CRP. In women, this association was not observed. In Hispanic participants, each additional ACPA was associated with 0.3±0.2% (p=0.049) higher IL-6 and 0.8±0.3% (p=0.010) higher CRP; in Caucasian participants, each additional ACPA was associated with 0.4±0.2% (p=0.014) higher IL-6 and 0.6±0.3% (p=0.026) higher CRP. This association was not observed in Chinese or African American participants. Conclusion: In a multi-ethnic community-dwelling population, higher number of ACPA was associated with higher IL-6 and CRP.