Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model.

Exercise training is considered a non-pharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with Amyotrophic Lateral Sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete four weeks of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimes need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.

Aspects of human uterine creatine metabolism during the menstrual cycle and at term pregnancy†.

Creatine metabolism likely contributes to energy homeostasis in the human uterus, but whether this organ synthesizes creatine and whether creatine metabolism is adjusted throughout the menstrual cycle and with pregnancy are largely unknown. This study determined endometrial protein expression of creatine-synthesizing enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), creatine kinase (CKBB), and the creatine transporter (SLC6A8) throughout the menstrual cycle in fertile and primary infertile women. It also characterized creatine metabolism at term pregnancy, measuring aspects of creatine metabolism in myometrial and decidual tissue. In endometrial samples, AGAT, GAMT, SLC6A8, and CKBB were expressed in glandular and luminal epithelial cells. Except for SLC6A8, the other proteins were also located in stromal cells. Irrespective of fertility, AGAT, GAMT, and SLC6A8 high-intensity immunohistochemical staining was greatest in the early secretory phase of the menstrual cycle. During the proliferative phase, staining for SLC6A8 protein was greater (P = 0.01) in the primary infertile compared with the fertile group. Both layers of the term pregnant uterus contained creatine, phosphocreatine, guanidinoacetic acid, arginine, glycine, and methionine; detectable gene and protein expression of AGAT, GAMT, CKBB, and ubiquitous mitochondrial CK (uMt-CK); and gene expression of SLC6A8. The proteins AGAT, GAMT, CKBB, and SLC6A8 were uniformly distributed in the myometrium and localized to the decidual glands. In conclusion, endometrial tissue has the capacity to produce creatine and its capacity is highest around the time of fertilization and implantation. Both layers of the term pregnant uterus also contained all the enzymatic machinery and substrates of creatine metabolism.

Maternal plasma vitamin D levels across pregnancy are not associated with neonatal birthweight: findings from an Australian cohort study of low-risk pregnant women.

BACKGROUND: In utero environments can be highly influential in contributing to the development of offspring obesity. Specifically, vitamin D deficiency during pregnancy is associated with adverse maternal and child health outcomes, however its relationship with offspring obesity remains unclear. We assessed maternal vitamin D status across pregnancy, change in plasma vitamin D concentrations and associations with neonatal birthweight, macrosomia and large for gestational age. METHODS: Women (n = 221) aged 18-40 years with singleton (low-risk) pregnancies, attending antenatal clinics at a tertiary-level maternity hospital were recruited at 10-20 weeks gestation. Medical history, maternal weight and blood samples at three antenatal clinic visits were assessed; early (15 ± 3 weeks), mid (27 ± 2 weeks) and late (36 ± 1 weeks) gestation. Maternal 25(OH)D was analysed from stored plasma samples via liquid chromatography-tandem mass spectrometry (LC/MS/MS). Neonatal growth parameters were collected at birth. Unadjusted and adjusted linear and logistic regression assessed associations of maternal vitamin D with birthweight, macrosomia and large for gestational age. RESULTS: Mean plasma 25(OH)D increased from early (83.8 ± 22.6 nmol/L) to mid (96.5 ± 28.9 nmol/L) and late (100.8 ± 30.8 nmol/L) gestation. Overall 98% of women were taking vitamin D-containing supplements throughout their pregnancy. Prevalence of vitamin D deficiency (25(OH)D < 50 nmol/L) was 6.5%, 6.3% and 6.8% at early, mid and late pregnancy respectively. No statistically significant association was found between 25(OH)D or vitamin D deficiency at any timepoint with neonatal birthweight, macrosomia or large for gestational age. CONCLUSIONS: Prevalence of vitamin D deficiency was low in this cohort of pregnant women and likely related to the high proportion of women taking vitamin D supplements during pregnancy. Maternal 25(OH)D did not impact offspring birth weight or birth size. Future studies in high-risk pregnant populations are needed to further assess maternal vitamin D status and factors in utero which promote early life obesity.

Long non-coding RNA Tug1 modulates mitochondrial and myogenic responses to exercise in skeletal muscle.

BACKGROUND: Mitochondria have an essential role in regulating metabolism and integrate environmental and physiological signals to affect processes such as cellular bioenergetics and response to stress. In the metabolically active skeletal muscle, mitochondrial biogenesis is one important component contributing to a broad set of mitochondrial adaptations occurring in response to signals, which converge on the biogenesis transcriptional regulator peroxisome proliferator-activated receptor coactivator 1-alpha (PGC-1α), and is central to the beneficial effects of exercise in skeletal muscle. We investigated the role of long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1), which interacts with PGC-1α in regulating transcriptional responses to exercise in skeletal muscle. RESULTS: In human skeletal muscle, TUG1 gene expression was upregulated post-exercise and was also positively correlated with the increase in PGC-1α gene expression (PPARGC1A). Tug1 knockdown (KD) in differentiating mouse myotubes led to decreased Ppargc1a gene expression, impaired mitochondrial respiration and morphology, and enhanced myosin heavy chain slow isoform protein expression. In response to a Ca2+-mediated stimulus, Tug1 KD prevented an increase in Ppargc1a expression. RNA sequencing revealed that Tug1 KD impacted mitochondrial Ca2+ transport genes and several downstream PGC-1α targets. Finally, Tug1 KD modulated the expression of ~300 genes that were upregulated in response to an in vitro model of exercise in myotubes, including genes involved in regulating myogenesis. CONCLUSIONS: We found that TUG1 is upregulated in human skeletal muscle after a single session of exercise, and mechanistically, Tug1 regulates transcriptional networks associated with mitochondrial calcium handling, muscle differentiation and myogenesis. These data demonstrate that lncRNA Tug1 exerts regulation over fundamental aspects of skeletal muscle biology and response to exercise stimuli.

Acute Effects of High-Intensity Aerobic Exercise on Motor Cortical Excitability and Inhibition in Sedentary Adults.

Transcranial magnetic stimulation studies have demonstrated increased cortical facilitation and reduced inhibition following aerobic exercise, even when examining motor regions separate to the exercised muscle group. These changes in brain physiology following exercise may create favorable conditions for adaptive plasticity and motor learning. One candidate mechanism behind these benefits is the increase in brain-derived neurotropic factor (BDNF) observed following exercise, which can be quantified from a venous blood draw. The aim of this study was to investigate changes in motor cortex excitability and inhibition of the upper limb, and circulating BDNF, following high-intensity interval training (HIIT) on a stationary bicycle. Nineteen sedentary adults participated in a randomized crossover design study involving a single bout of high-intensity interval cycling for 20 min or seated rest. Venous blood samples were collected, and transcranial magnetic stimulation (TMS) was used to stimulate the extensor carpi radialis (ECR), where motor evoked potentials (MEP) were recorded pre- and post-condition. Following exercise, there was a significant increase (29.1%, p < 0.001) in corticospinal excitability measured at 120% of resting motor threshold (RMT) and a reduction in short-interval cortical inhibition (SICI quantified as 86.2% increase in the SICI ratio, p = 0.002). There was a non-significant (p = 0.125) 23.6% increase in BDNF levels. Collectively, these results reflect a net reduction in gamma aminobutyric acid (GABA)ergic synaptic transmission and increased glutamatergic facilitation, resulting in increased corticospinal excitability. This study supports the notion that acute high-intensity exercise provides a potent stimulus for inducing cortical neuroplasticity, which may support enhanced motor learning.

Muscle Adaptations to Heavy-Load and Blood Flow Restriction Resistance Training Methods.

Resistance-based blood flow restriction training (BFRT) improves skeletal muscle strength and size. Unlike heavy-load resistance training (HLRT), there is debate as to whether strength adaptations following BFRT interventions can be primarily attributed to concurrent muscle hypertrophy, as the magnitude of hypertrophy is often minor. The present study aimed to investigate the effect of 7 weeks of BFRT and HLRT on muscle strength and hypertrophy. The expression of protein growth markers from muscle biopsy samples was also measured. Male participants were allocated to moderately heavy-load training (HL; n = 9), low-load BFRT (LL + BFR; n = 8), or a control (CON; n = 9) group to control for the effect of time. HL and LL + BFR completed 21 training sessions (3 d.week-1) comprising bilateral knee extension and knee flexion exercises (HL = 70% one-repetition maximum (1-RM), LL + BFR = 20% 1-RM + blood flow restriction). Bilateral knee extension and flexion 1-RM strength were assessed, and leg muscle CSA was measured via peripheral quantitative computed tomography. Protein growth markers were measured in vastus lateralis biopsy samples taken pre- and post the first and last training sessions. Biopsy samples were also taken from CON at the same time intervals as HL and LL + BFR. Knee extension 1-RM strength increased in HL (19%) and LL + BFR (19%) but not CON (2%; p < 0.05). Knee flexion 1-RM strength increased similarly between all groups, as did muscle CSA (50% femur length; HL = 2.2%, LL + BFR = 3.0%, CON = 2.1%; TIME main effects). 4E-BP1 (Thr37/46) phosphorylation was lower in HL and LL + BFR immediately post-exercise compared with CON in both sessions (p < 0.05). Expression of other growth markers was similar between groups (p > 0.05). Overall, BFRT and HLRT improved muscle strength and size similarly, with comparable changes in intramuscular protein growth marker expression, both acutely and chronically, suggesting the activation of similar anabolic pathways. However, the low magnitude of muscle hypertrophy was not significantly different to the non-training control suggesting that strength adaptation following 7 weeks of BFRT is not driven by hypertrophy, but rather neurological adaptation.

miR-23a suppression accelerates functional decline in the rNLS8 mouse model of TDP-43 proteinopathy.

Skeletal muscle dysfunction may contribute to the progression and severity of amyotrophic lateral sclerosis (ALS). In the present study, we characterized the skeletal muscle pathophysiology in an inducible transgenic mouse model (rNLS8) that develops a TAR-DNA binding protein (TDP-43) proteinopathy and ALS-like neuropathology and disease progression; representative of >90% of all familial and sporadic ALS cases. As we previously observed elevated levels of miR-23a in skeletal muscle of patients with familial and sporadic ALS, we also investigated the effect of miR-23a suppression on skeletal muscle pathophysiology and disease severity in rNLS8 mice. Five weeks after disease onset TDP-43 protein accumulation was observed in tibialis anterior (TA), quadriceps (QUAD) and diaphragm muscle lysates and associated with skeletal muscle atrophy. In the TA muscle TDP-43 was detected in muscle fibres that appeared atrophied and angular in appearance and that also contained ß-amyloid aggregates. These fibres were also positive for neural cell adhesion molecule (NCAM), but not embryonic myosin heavy chain (eMHC), indicating TDP-43/ ß-amyloid localization in denervated muscle fibres. There was an upregulation of genes associated with myogenesis and NMJ degeneration and a decrease in the MURF1 atrophy-related protein in skeletal muscle. Suppression of miR-23a impaired rotarod performance and grip strength and accelerated body weight loss during early stages of disease progression. This was associated with increased AchRα mRNA expression and decreased protein levels of PGC-1α. The TDP-43 proteinopathy-induced impairment of whole body and skeletal muscle functional performance is associated with muscle wasting and elevated myogenic and NMJ stress markers. Suppressing miR-23a in the rNLS8 mouse model of ALS contributes to an early acceleration of disease progression as measured by decline in motor function.

Sensitivity to behavioral stress impacts disease pathogenesis in dystrophin-deficient mice.

Mutation to the gene encoding dystrophin can cause Duchenne muscular dystrophy (DMD) and increase the sensitivity to stress in vertebrate species, including the mdx mouse model of DMD. Behavioral stressors can exacerbate some dystrophinopathy phenotypes of mdx skeletal muscle and cause hypotension-induced death. However, we have discovered that a subpopulation of mdx mice present with a wildtype-like response to mild (forced downhill treadmill exercise) and moderate (scruff restraint) behavioral stressors. These "stress-resistant" mdx mice are more physically active, capable of super-activating the hypothalamic-pituitary-adrenal and renin-angiotensin-aldosterone pathways following behavioral stress and they express greater levels of mineralocorticoid and glucocorticoid receptors in striated muscle relative to "stress-sensitive" mdx mice. Stress-resistant mdx mice also presented with a less severe striated muscle histopathology and greater exercise and skeletal muscle oxidative capacity at rest. Most interestingly, female mdx mice were more physically active following behavioral stressors compared to male mdx mice; a response abolished after ovariectomy and rescued with estradiol. We demonstrate that the response to behavioral stress greatly impacts disease severity in mdx mice suggesting the management of stress in patients with DMD be considered as a therapeutic approach to ameliorate disease progression.

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.

The Effects of an Acute "Train-Low" Nutritional Protocol on Markers of Recovery Optimization in Endurance-Trained Male Athletes.

PURPOSE: This study aimed to determine the effects of an acute "train-low" nutritional protocol on markers of recovery optimization compared to standard recovery nutrition protocol. METHODS: After completing a 2-hour high-intensity interval running protocol, 8 male endurance athletes consumed a standard dairy milk recovery beverage (CHO; 1.2 g/kg body mass [BM] of carbohydrate and 0.4 g/kg BM of protein) and a low-carbohydrate (L-CHO; isovolumetric with 0.35 g/kg BM of carbohydrate and 0.5 g/kg BM of protein) dairy milk beverage in a double-blind randomized crossover design. Venous blood and breath samples, nude BM, body water, and gastrointestinal symptom measurements were collected preexercise and during recovery. Muscle biopsy was performed at 0 hour and 2 hours of recovery. Participants returned to the laboratory the following morning to measure energy substrate oxidation and perform a 1-hour distance test. RESULTS: The exercise protocol resulted in depletion of muscle glycogen stores (250 mmol/kg dry weight) and mild body-water losses (BM loss = 1.8%). Neither recovery beverage replenished muscle glycogen stores (279 mmol/kg dry weight) or prevented a decrease in bacterially stimulated neutrophil function (-21%). Both recovery beverages increased phosphorylation of mTORSer2448 (main effect of time = P < .001) and returned hydration status to baseline. A greater fold increase in p-GSK-3ßSer9/total-GSK-3ß occurred on CHO (P = .012). Blood glucose (P = .005) and insulin (P = .012) responses were significantly greater on CHO (618 mmol/L per 2 h and 3507 µIU/mL per 2 h, respectively) compared to L-CHO (559 mmol/L per 2 h and 1147 µIU/mL per 2 h, respectively). Rates of total fat oxidation were greater on CHO, but performance was not affected. CONCLUSION: A lower-carbohydrate recovery beverage consumed after exercise in a "train-low" nutritional protocol does not negatively impact recovery optimization outcomes.

Reactive oxygen species in exercise and insulin resistance: Working towards personalized antioxidant treatment.

Reactive oxygen species (ROS) are well known for their role in insulin resistance and the development of cardiometabolic disease including type 2 diabetes mellitus (T2D). Conversely, evidence supports the notion that ROS are a necessary component for glucose cell transport and adaptation to physiological stress including exercise and muscle contraction. Although genetic rodent models and cell culture studies indicate antioxidant treatment to be an effective strategy for targeting ROS to promote health, human findings are largely inconsistent. In this review we discuss human research that has investigated antioxidant treatment and glycemic control in the context of health (healthy individuals and during exercise) and disease (insulin resistance and T2D). We have identified key factors that are likely to influence the effectiveness of antioxidant treatment: 1) the context of treatment including whether oxidative distress or eustress is present (e.g., hyperglycemia/lipidaemia or during exercise and muscle contraction); 2) whether specific endogenous antioxidant deficiencies are identified (redox screening); 3) whether antioxidant treatment is specifically designed to target and restore identified deficiencies (antioxidant specificity); 4) and the bioavailability and bioactivity of the antioxidant which are influenced by treatment dose, duration, and method of administration. The majority of human research has failed to account for these factors, limiting their ability to robustly test the effectiveness of antioxidants for health promotion and disease prevention. We propose that a modern "redox screening" and "personalized antioxidant treatment" approach is required to robustly explore redox regulation of human physiology and to elicit more effective antioxidant treatment in humans.

Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health.

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research "road forward" to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes.

Assessing Overall Exercise Recovery Processes Using Carbohydrate and Carbohydrate-Protein Containing Recovery Beverages.

We compared the impact of two different, but commonly consumed, beverages on integrative markers of exercise recovery following a 2 h high intensity interval exercise (i.e., running 70-80% V̇O2 max intervals and interspersed with plyometric jumps). Participants (n = 11 males, n = 6 females) consumed a chocolate flavored dairy milk beverage (CM: 1.2 g carbohydrate/kg BM and 0.4 g protein/kg BM) or a carbohydrate-electrolyte beverage (CEB: isovolumetric with 0.76 g carbohydrate/kg BM) after exercise, in a randomized-crossover design. The recovery beverages were provided in three equal boluses over a 30 min period commencing 1 h post-exercise. Muscle biopsies were performed at 0 h and 2 h in recovery. Venous blood samples, nude BM and total body water were collected before and at 0, 2, and 4 h recovery. Gastrointestinal symptoms and breath hydrogen (H2) were collected before exercise and every 30 min during recovery. The following morning, participants returned for performance assessment. In recovery, breath H2 reached clinical relevance of >10 ppm following consumption of both beverages, in adjunct with high incidence of gastrointestinal symptoms (70%), but modest severity. Blood glucose response was greater on CEB vs. CM (P < 0.01). Insulin response was greater on CM compared with CEB (P < 0.01). Escherichia coli lipopolysaccharide stimulated neutrophil function reduced on both beverages (49%). p-GSK-3ß/total-GSK-3ß was greater on CM compared with CEB (P = 0.037); however, neither beverage achieved net muscle glycogen re-storage. Phosphorylation of mTOR was greater on CM than CEB (P < 0.001). Fluid retention was lower (P = 0.038) on CEB (74.3%) compared with CM (82.1%). Physiological and performance outcomes on the following day did not differ between trials. Interconnected recovery optimization markers appear to respond differently to the nutrient composition of recovery nutrition, albeit subtly and with individual variation. The present findings expand on recovery nutrition strategies to target functionality and patency of the gastrointestinal tract as a prerequisite to assimilation of recovery nutrition, as well as restoration of immunocompetency.

Reallocating sedentary time with total physical activity and physical activity bouts in children: Associations with cardiometabolic biomarkers.

This cross-sectional study examined theoretical effects of reallocating sedentary time (SED) with total physical activity, and physical activity bouts of varying intensities, on children's cardiometabolic biomarkers. Baseline data from the Transform-Us! trial (Melbourne, Australia) was used. Participant data were included if accelerometer and blood biomarker data were complete (n = 169; 8.7 [0.4] years; 56% girls). Isotemporal substitution models assessed the impact of replacing 10 minutes of SED with 10 minutes of total physical activity or physical activity in bouts of varying intensities on cardiometabolic biomarkers. In adjusted models, replacing 10 minutes of SED with vigorous-intensity physical activity (VPA) was associated with lower triglycerides in the whole sample. Replacing SED with VPA was associated with better high-density lipoprotein cholesterol (HDL-C) and triglycerides in children with healthy weight. Replacing SED with MPA was associated with better homoeostatic model assessment of insulin resistance (HOMA-IR) and HDL-C, in children with healthy weight and overweight, respectively. Substituting SED with VPA specifically accumulated in ≥1-min bouts was detrimentally associated with HOMA-IR in children with healthy weight but beneficially with the cardiometabolic summary score in the overweight sample. This suggests that replacing SED with MPA or VPA may have some benefits on cardiometabolic health.

Is replacing sedentary time with bouts of physical activity associated with inflammatory biomarkers in children?

This study aimed to investigate the theoretical impact of reallocating a specific amount of sedentary time with an equal amount of (a) total and (b) ≥1-minute bout-accumulated time spent in different activity intensities, on inflammatory biomarkers in 8- to 9-year-old children. Accelerometry and inflammatory biomarker baseline data from the Transform-Us! Study (complete cases n = 149) were utilized. Isotemporal linear models with the Gaussian distribution and identity link functions were used to assess associations between the activity replacements and seven individual inflammatory biomarkers, including C-reactive protein (CRP), and Interleukin (IL)-2, IL-6, IL-8, and IL-10, as well as combined inflammatory and pro-inflammatory composite scores. Eighty-five percent of children met physical activity recommendations. Replacing 10 minutes of sedentary time per day with VPA, regardless of how this was accumulated, was beneficially associated with CRP and both combined composite scores. In contrast, replacing 10 min/day of sedentary time with ≥ 1-minute MPA bouts was detrimentally associated with CRP and the inflammatory composite score. Substitutions with other activity intensities were not significantly associated with any individual inflammatory biomarkers, or combined inflammatory and pro-inflammatory composite scores. In healthy and active school-aged children, evidence of the theoretical impact of replacing sedentary time with physical activity, regardless of intensity or accumulation, on markers of systemic inflammation was limited. Longitudinal research is needed to investigate the long-term impacts of reallocating sedentary time with physical activity, and particularly VPA, for inflammatory biomarkers in children, including those with increased risk of inflammation.

Mobilizing serum factors and immune cells through exercise to counteract age-related changes in cancer risk.

An increasing body of evidence suggests that age-related immune changes and chronic inflammation contribute to cancer development. Recognizing that exercise has protective effects against cancer, promotes immune function, and beneficially modulates inflammation with ageing, this review outlines the current evidence indicating an emerging role for exercise immunology in preventing and treating cancer in older adults. A specific focus is on data suggesting that muscle- derived cytokines (myokines) mediate anti-cancer effects through promoting immunosurveillance against tumourigenesis or inhibiting cancer cell viability. Previous studies suggested that the exercise-induced release of myokines and other endocrine factors into the blood increases the capacity of blood serum to inhibit cancer cell growth in vitro. However, little is known about whether this effect is influenced by ageing. Prostate cancer is the second most common cancer in men. We therefore examined the effects of serum collected before and after exercise from healthy young and older men on the metabolic activity of androgen-responsive LNCaP and androgen-unresponsive PC3 prostate cancer cells. Exercise-conditioned serum collected from the young group did not alter cell metabolic activity, whereas post-exercise serum (compared with pre-exercise serum) from the older men inhibited the metabolic activity of LNCaP cancer cells. Serum levels of candidate cancer-inhibitory myokines oncostatin M and osteonectin increased in both age groups following exercise. Serum testosterone increased only in the younger men postexercise, potentially attenuating inhibitory effects of myokines on the LNCaP cell viability. The data from our study and the evidence in this review suggest that mobilizing serum factors and immune cells may be a key mechanism of how exercise counteracts cancer in the older population.

Does the Nutritional Composition of Dairy Milk Based Recovery Beverages Influence Post-exercise Gastrointestinal and Immune Status, and Subsequent Markers of Recovery Optimisation in Response to High Intensity Interval Exercise?

This study aimed to determine the effects of flavored dairy milk based recovery beverages of different nutrition compositions on markers of gastrointestinal and immune status, and subsequent recovery optimisation markers. After completing 2 h high intensity interval running, participants (n = 9) consumed a whole food dairy milk recovery beverage (CM, 1.2 g/kg body mass (BM) carbohydrate and 0.4 g/kg BM protein) or a dairy milk based supplement beverage (MBSB, 2.2 g/kg BM carbohydrate and 0.8 g/kg BM protein) in a randomized crossover design. Venous blood samples, body mass, body water, and breath samples were collected, and gastrointestinal symptoms (GIS) were measured, pre- and post-exercise, and during recovery. Muscle biopsies were performed at 0 and 2 h of recovery. The following morning, participants returned to the laboratory to assess performance outcomes. In the recovery period, carbohydrate malabsorption (breath H2 peak: 49 vs. 24 ppm) occurred on MBSB compared to CM, with a trend toward greater gut discomfort. No difference in gastrointestinal integrity (i.e., I-FABP and sCD14) or immune response (i.e., circulating leukocyte trafficking, bacterially-stimulated neutrophil degranulation, and systemic inflammatory profile) markers were observed between CM and MBSB. Neither trial achieved a positive rate of muscle glycogen resynthesis [-25.8 (35.5) mmol/kg dw/h]. Both trials increased phosphorylation of intramuscular signaling proteins. Greater fluid retention (total body water: 86.9 vs. 81.9%) occurred on MBSB compared to CM. Performance outcomes did not differ between trials. The greater nutrient composition of MBSB induced greater gastrointestinal functional disturbance, did not prevent the post-exercise reduction in neutrophil function, and did not support greater overall acute recovery.

Placental creatine metabolism in cases of placental insufficiency and reduced fetal growth.

Creatine is a metabolite involved in cellular energy homeostasis. In this study, we examined placental creatine content, and expression of the enzymes required for creatine synthesis, transport and the creatine kinase reaction, in pregnancies complicated by low birthweight. We studied first trimester chorionic villus biopsies (CVBs) of small for gestational age (SGA) and appropriately grown infants (AGA), along with third trimester placental samples from fetal growth restricted (FGR) and healthy gestation-matched controls. Placental creatine and creatine precursor (guanidinoacetate-GAA) levels were measured. Maternal and cord serum from control and FGR pregnancies were also analyzed for creatine concentration. mRNA expression of the creatine transporter (SLC6A8); synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT); mitochondrial (mtCK) and cytosolic (BBCK) creatine kinases; and amino acid transporters (SLC7A1 & SLC7A2) was assessed in both CVBs and placental samples. Protein levels of AGAT (arginine:glycine aminotransferase), GAMT, mtCK and BBCK were also measured in placental samples. Key findings; total creatine content of the third trimester FGR placentae was 43% higher than controls. The increased creatine content of placental tissue was not reflected in maternal or fetal serum from FGR pregnancies. Tissue concentrations of GAA were lower in the third trimester FGR placentae compared to controls, with lower GATM and GAMT mRNA expression also observed. No differences in the mRNA expression of GATM, GAMT or SLC6A8 were observed between CVBs from SGA and AGA pregnancies. These results suggest placental creatine metabolism in FGR pregnancies is altered in late gestation. The relevance of these changes on placental bioenergetics should be the focus of future investigations.

Dietary Patterns in New Zealand Women: Evaluating Differences in Body Composition and Metabolic Biomarkers.

The combinations of food consumed together (dietary patterns) may have a greater influence on health than nutrients or food groups consumed independently. This study investigated the relationship between dietary patterns, body composition and metabolic biomarkers of premenopausal New Zealand women from three ethnic groups. In total, 408 New Zealand European, Maori and Pacific women aged 16-45 years participated in the Women's EXPLORE (EXamining Predictors Linking Obesity Related Elements) study. Participants completed a 220-item food frequency questionnaire. Several body composition parameters and metabolic biomarkers were measured. Dietary patterns were extracted by principal component analysis and dietary pattern scores were categorised into tertiles to assess links with other measured parameters. Women with higher scores for the 'refined and processed' pattern were younger, had higher body mass index, total body fat, plasma leptin and plasma insulin (p < 0.001), and lower plasma ghrelin levels (p < 0.05) than women with lower scores. In addition, more Maori (51%) and Pacific (68%) women followed the 'refined and processed' pattern, while more New Zealand European women (40%) followed the 'sweet and savoury snacking' pattern. These data show that dietary pattern analysis is a useful tool to assess links between diet and metabolic health. It further reveals interesting ethnic group-specific differences in dietary pattern use.

Phosphatidylserine decarboxylase is critical for the maintenance of skeletal muscle mitochondrial integrity and muscle mass.

OBJECTIVE: Phosphatidylethanolamine (PtdEtn) is a major phospholipid in mammals. It is synthesized via two pathways, the CDP-ethanolamine pathway in the endoplasmic reticulum and the phosphatidylserine (PtdSer) decarboxylase (PSD) pathway in the mitochondria. While the CDP-ethanolamine pathway is considered the major route for PtdEtn synthesis in most mammalian tissues, little is known about the importance of the PSD pathway in vivo, especially in tissues enriched with mitochondria such as skeletal muscle. Therefore, we aimed to examine the role of the mitochondrial PSD pathway in regulating PtdEtn homeostasis in skeletal muscle in vivo. METHODS: To determine the functional significance of this pathway in skeletal muscle in vivo, an adeno-associated viral vector approach was employed to knockdown PSD expression in skeletal muscle of adult mice. Muscle lipid and metabolite profiling was performed using mass spectrometry. RESULTS: PSD knockdown disrupted muscle phospholipid homeostasis leading to an ∼25% reduction in PtdEtn and an ∼45% increase in PtdSer content. This was accompanied by the development of a severe myopathy, evident by a 40% loss in muscle mass as well as extensive myofiber damage as shown by increased DNA synthesis and central nucleation. In addition, PSD knockdown caused marked accumulation of abnormally appearing mitochondria that exhibited severely disrupted inner membrane integrity and reduced OXPHOS protein content. CONCLUSIONS: The PSD pathway has a significant role in maintaining phospholipid homeostasis in adult skeletal muscle. Moreover, PSD is essential for maintenance of mitochondrial integrity and skeletal muscle mass.