Higher levels of physical activity are associated with reduced tethering and migration of pro-inflammatory monocytes in males with central obesity.

Despite evidence that monocyte migration is accentuated by central adiposity, the impact of physical activity (PA) and exercise, particularly in the post-prandial state, on limiting migration are not established. We hypothesised that PA and a single bout of walking exercise would be associated with reduced ex vivo monocyte tethering and migration in middleaged males with central obesity (CO). Objective levels of PA were measured for 7 days in lean males (LE, N=12, mean (SD) age 39 (10) years, waist circumference 81.0 (6.3) cm) and males with CO (N=12, mean (SD) age 40 (9) years, waist circumference 115.3 (13.9) cm), followed by donation of a fasted blood sample. On the same day, CO undertook a bout of walking exercise, before donation of a second fasted blood sample. An ex vivo assay, coupled to flow cytometry, determined tethering and migration of classical, intermediate, and non-classical monocytes. C-C and CXC chemokine receptor (CCR2, CCR5 and CX3CR1) expression were also determined on total and classical monocytes. Monocyte subsets (total, classical, intermediate and CCR2+ monocytes), metabolic (glucose and lipids) and inflammatory (C-reactive protein) markers were greater in CO vs. LE (lower highdensity lipoprotein); however, adjustments for PA mitigated group differences for glucose, lipids, and monocyte subsets. Ex vivo tethering and migration (absolute and relative) of most monocyte subsets was greater in CO vs LE. Relative monocyte tethering and migration was largely not influenced by PA; however, higher PA was associated with reduced absolute migration and tethering of CD16 expressing monocytes in CO. Prior walking had no impact on these variables. These results highlight that regular PA, not single exercise bouts may limit the migration of pro-inflammatory monocytes in CO. These changes may relate to physiological parameters in blood (i.e. number of cells and their adhesion), rather than differences in chemokine receptor expression.

PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response.

The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response.

Physiological Roles of Carnosine in Myocardial Function and Health.

Carnosine is a pleiotropic histidine-containing dipeptide synthesized from ß-alanine and l-histidine, with the intact dipeptide and constituent amino acids being available from the diet. The therapeutic application of carnosine in myocardial tissue is promising, with carnosine playing a potentially beneficial role in both healthy and diseased myocardial models. This narrative review discusses the role of carnosine in myocardial function and health, including an overview of the metabolic pathway of carnosine in the myocardial tissue, the roles carnosine may play in the myocardium, and a critical analysis of the literature, focusing on the effect of exogenous carnosine and its precursors on myocardial function. By so doing, we aim to identify current gaps in the literature, thereby identifying considerations for future research.

A randomized controlled trial to isolate the effects of fasting and energy restriction on weight loss and metabolic health in lean adults.

Intermittent fasting may impart metabolic benefits independent of energy balance by initiating fasting-mediated mechanisms. This randomized controlled trial examined 24-hour fasting with 150% energy intake on alternate days for 3 weeks in lean, healthy individuals (0:150; n = 12). Control groups involved a matched degree of energy restriction applied continuously without fasting (75% energy intake daily; 75:75; n = 12) or a matched pattern of fasting without net energy restriction (200% energy intake on alternate days; 0:200; n = 12). Primary outcomes were body composition, components of energy balance, and postprandial metabolism. Daily energy restriction (75:75) reduced body mass (-1.91 ± 0.99 kilograms) almost entirely due to fat loss (-1.75 ± 0.79 kilograms). Restricting energy intake via fasting (0:150) also decreased body mass (-1.60 ± 1.06 kilograms; P = 0.46 versus 75:75) but with attenuated reductions in body fat (-0.74 ± 1.32 kilograms; P = 0.01 versus 75:75), whereas fasting without energy restriction (0:200) did not significantly reduce either body mass (-0.52 ± 1.09 kilograms; P ≤ 0.04 versus 75:75 and 0:150) or fat mass (-0.12 ± 0.68 kilograms; P ≤ 0.05 versus 75:75 and 0:150). Postprandial indices of cardiometabolic health and gut hormones, along with the expression of key genes in subcutaneous adipose tissue, were not statistically different between groups (P > 0.05). Alternate-day fasting less effectively reduces body fat mass than a matched degree of daily energy restriction and without evidence of fasting-specific effects on metabolic regulation or cardiovascular health.