Sex-based differences in Muscle Stem Cell Regulation Following Exercise.

ABSTRACT: Sexual dimorphism, driven by the sex hormones testosterone and estrogen, influences body composition, muscle fiber type, and inflammation. Research related to muscle stem cell (MuSC) responses to exercise has mainly focused on males. We propose a novel hypothesis that there are sex-based differences in MuSC regulation following exercise, such that males have more MuSCs while females demonstrate a greater capacity for regeneration.

Radiation induces long-term muscle fibrosis and promotes a fibrotic phenotype in fibro-adipogenic progenitors.

BACKGROUND: Radiation-induced muscle pathology, characterized by muscle atrophy and fibrotic tissue accumulation, is the most common debilitating late effect of therapeutic radiation exposure particularly in juvenile cancer survivors. In healthy muscle, fibro/adipogenic progenitors (FAPs) are required for muscle maintenance and regeneration, while in muscle pathology FAPs are precursors for exacerbated extracellular matrix deposition. However, the role of FAPs in radiation-induced muscle pathology has not previously been explored. METHODS: Four-week-old Male CBA or C57Bl/6J mice received a single dose (16 Gy) of irradiation (IR) to a single hindlimb with the shielded contralateral limb (CLTR) serving as a non-IR control. Mice were sacrificed 3, 7, 14 (acute IR response), and 56 days post-IR (long-term IR response). Changes in skeletal muscle morphology, myofibre composition, muscle niche cellular dynamics, DNA damage, proliferation, mitochondrial respiration, and metabolism and changes in progenitor cell fate where assessed. RESULTS: Juvenile radiation exposure resulted in smaller myofibre cross-sectional area, particularly in type I and IIA myofibres (P < 0.05) and reduced the proportion of type I myofibres (P < 0.05). Skeletal muscle fibrosis (P < 0.05) was evident at 56 days post-IR. The IR-limb had fewer endothelial cells (P < 0.05) and fibro-adipogenic progenitors (FAPs) (P < 0.05) at 56 days post-IR. Fewer muscle satellite (stem) cells were detected at 3 and 56 days in the IR-limb (P < 0.05). IR induced FAP senescence (P < 0.05), increased their fibrogenic differentiation (P < 0.01), and promoted their glycolytic metabolism. Further, IR altered the FAP secretome in a manner that impaired muscle satellite (stem) cell differentiation (P < 0.05) and fusion (P < 0.05). CONCLUSIONS: Our study suggests that following juvenile radiation exposure, FAPs contribute to long-term skeletal muscle atrophy and fibrosis. These findings provide rationale for investigating FAP-targeted therapies to ameliorate the negative late effects of radiation exposure in skeletal muscle.

Resistance and endurance exercise training improves muscle mass and the inflammatory/fibrotic transcriptome in a rhabdomyosarcoma model.

BACKGROUND: Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma that most often develops in children. Chemoradiation therapy is a standard treatment modality; however, the detrimental long-term skeletal muscle consequences of this therapy in juvenile cancer survivors include muscle atrophy and fibrosis resulting in decreased physical performance. Using a novel model of murine resistance and endurance exercise training, we investigate its role in preventing the long-term effects of juvenile RMS plus therapy. METHODS: Four-week-old male (n = 10) and female (n = 10) C57Bl/6J mice were injected with M3-9-M RMS cell into the left gastrocnemius with the right limb serving as an internal control (CON). Mice received a systemic vincristine injection and then five doses of 4.8 Gy of gamma radiation localized to the left hindlimb (RMS + Tx). Mice were then randomly divided into either sedentary (SED) or resistance and endurance exercise training (RET) groups. Changes in exercise performance, body composition, myocellular adaptations and the inflammatory/fibrotic transcriptome were assessed. RESULTS: RET improved endurance performance (P < 0.0001) and body composition (P = 0.0004) compared to SED. RMS + Tx resulted in significantly lower muscle weight (P = 0.015) and significantly smaller myofibre cross-sectional area (CSA) (P = 0.014). Conversely, RET resulted in significantly higher muscle weight (P = 0.030) and significantly larger Type IIA (P = 0.014) and IIB (P = 0.015) fibre CSA. RMS + Tx resulted in significantly more muscle fibrosis (P = 0.028), which was not prevented by RET. RMS + Tx resulted in significantly fewer mononuclear cells (P < 0.05) and muscle satellite (stem) cells (MuSCs) (P < 0.05) and significantly more immune cells (P < 0.05) than CON. RET resulted in significantly more fibro-adipogenic progenitors (P < 0.05), a trend for more MuSCs (P = 0.076) than SED and significantly more endothelial cells specifically in the RMS + Tx limb. Transcriptomic changes revealed significantly higher expression of inflammatory and fibrotic genes in RMS + Tx, which was prevented by RET. In the RMS + Tx model, RET also significantly altered expression of genes involved in extracellular matrix turnover. CONCLUSIONS: Our study suggests that RET preserves muscle mass and performance in a model of juvenile RMS survivorship while partially restoring cellular dynamics and the inflammatory and fibrotic transcriptome.

Dietary fiber intake and fecal short-chain fatty acid concentrations are associated with lower plasma lipopolysaccharide-binding protein and inflammation.

Consuming adequate dietary fiber is a promising strategy for reducing systemic inflammation. The objective was to evaluate relationships between dietary fiber intake, markers of metabolic endotoxemia, and systemic inflammation in adults. This was a cross-sectional study of 129 healthy participants (age 33.6 ± 6.1 yr, BMI 30.5 ± 6.9 kg/m2). Dietary fiber intake was assessed by food frequency questionnaire. Adiposity was measured using dual-energy X-ray absorptiometry (DXA). Fecal short-chain fatty acids (SCFA) were quantified using gas chromatography-mass spectrometry. Fecal microbiota sequence data (V4 region, 16S rRNA gene) were analyzed using DADA2 and QIIME2. Inflammatory cytokines were assessed with enzyme-linked immunosorbent assays; flow cytometry was conducted for monocyte surface marker quantification. Bivariate correlations and generalized step-wise linear modeling were used for statistical analyses. Plasma C-reactive protein (CRP) and interleukin (IL)-6 concentrations were positively related to whole body (CRP r = 0.45, P = <0.0001; IL-6 r = 0.34, P = 0.0002) and visceral adiposity (CRP r = 0.33, P = 0.0003; IL-6 r = 0.38, P = 0.0002). Plasma lipopolysaccharide-binding protein (LBP) concentrations were inversely related to dietary fiber intake (r = -0.22, P = 0.03) and fecal SCFA (acetate r = -0.25, P = 0.01; propionate r = -0.28, P = 0.003; butyrate r = -0.23, P = 0.02). Whole body adiposity, dietary fiber, and fecal SCFA were the most predictive of plasma LBS-BP concentrations. Novel findings included associations between dietary fiber intake, the gastrointestinal microbiota, and systemic inflammation.NEW & NOTEWORTHY Dietary fiber intake may reduce the inflammation associated with obesity and metabolic disease. Our cross-sectional analysis revealed that dietary fiber intake and fecal short-chain fatty acids are inversely associated with lipopolysaccharide-binding protein, a marker of systemic inflammation. In addition, plasma interleukin-6 and C-reactive protein were positively related to markers of adiposity.

Sex-based comparisons of muscle cellular adaptations after 10 weeks of progressive resistance training in middle-aged adults.

Resistance training combined with adequate protein intake supports skeletal muscle strength and hypertrophy. These adaptations are supported by the action of muscle stem cells (MuSCs), which are regulated, in part, by fibro-adipogenic progenitors (FAPs) and circulating factors delivered through capillaries. It is unclear if middle-aged males and females have similar adaptations to resistance training at the cellular level. To address this gap, 27 (13 males, 14 females) middle-aged (40-64 yr) adults participated in 10 wk of whole body resistance training with dietary counseling. Muscle biopsies were collected from the vastus lateralis pre- and posttraining. Type II fiber cross-sectional area increased similarly with training in both sexes (P = 0.014). MuSC content was not altered with training; however, training increased PDGFRα+/CD90+ FAP content (P < 0.0001) and reduced PDGFRα+/CD90- FAP content (P = 0.044), independent of sex. The number of CD31+ capillaries per fiber also increased similarly in both sexes (P < 0.05). These results suggest that muscle fiber hypertrophy, stem/progenitor cell, and capillary adaptations are similar between middle-aged males and females in response to whole body resistance training.NEW & NOTEWORTHY We demonstrate that resistance training-induced increases in fiber hypertrophy, FAP content, and capillarization are similar between middle-aged males and females.

Cross-sectional analysis reveals COVID-19 pandemic community lockdown was linked to dysregulated cortisol and salivary alpha amylase in children.

The COVID-19 pandemic altered everyday life starting in March 2020. These alterations extended to the lives of children as their normal routines were disrupted by community lockdowns, online learning, limited in-person social contact, increased screen time, and reduced physical activity. Considerable research has investigated the physical health impact of COVID-19 infection, but far fewer studies have investigated the physiological impact of stressful pandemic-related changes to daily life, especially in children. The purpose of this study was to leverage an ongoing clinical trial to investigate physiological consequences associated with chronic stress of pandemic community lockdown on children. As a part of the clinical trial, children provided saliva samples. Saliva samples were analyzed for cortisol and salivary alpha amylase (sAA) content. This secondary cross-sectional analysis included 94 preadolescent children located within the Greater Boston, Massachusetts community. Children participated in the study either before, during, or following the pandemic community lockdown to form three groups for comparison. In response to chronic stress caused by the pandemic community lockdown, participants demonstrated dysregulation of fast-acting catecholamine response of the locus-coeruleus-norepinephrine system and slower-acting glucocorticoid response, resulting in an asymmetrical relationship of hypocortisolism (M = 0.78 ± 0.19 µg/mL, p < 0.001) paired with higher sAA (M = 12.73 ± 4.06 U/mL, p = 0.01). Results suggest that the abrupt COVID-19 disruption to daily life, including the stressful experience of community lockdown, had physiological effects on typically developing children. Further research is required to investigate mental health outcomes of children following the chronic stress of the pandemic community lockdown.

The role of exercise-and high fat diet-induced bone marrow extracellular vesicles in stress hematopoiesis.

Exercise and obesity regulate hematopoiesis, in part through alterations in cellular and soluble components of the bone marrow niche. Extracellular vesicles (EVs) are components of the bone marrow niche that regulate hematopoiesis; however, the role of exercise training or obesity induced EVs in regulating hematopoiesis remains unknown. To address this gap, donor EVs were isolated from control diet-fed, sedentary mice (CON-SED), control diet-fed exercise trained mice (CON-EX), high fat diet-fed, sedentary mice (HFD-SED), and high fat diet-fed, exercise trained mice (HFD-EX) and injected into recipient mice undergoing stress hematopoiesis. Hematopoietic and niche cell populations were quantified, and EV miRNA cargo was evaluated. EV content did not differ between the four groups. Mice receiving HFD-EX EVs had fewer hematopoietic stem cells (HSCs) (p < 0.01), long-term HSC (p < 0.05), multipotent progenitors (p < 0.01), common myeloid progenitors (p<0.01), common lymphoid progenitors (p < 0.01), and granulocyte-macrophage progenitors (p < 0.05), compared to mice receiving HFD-SED EVs. Similarly, mice receiving EX EVs had fewer osteoprogenitor cells compared to SED (p < 0.05) but enhanced mesenchymal stromal cell (MSC) osteogenic differentiation in vitro (p < 0.05) compared to SED EVs. HFD EVs enhanced mesenchymal stromal cell (MSC) adipogenesis in vitro (p < 0.01) compared to CON EVs. HFD-EX EVs had lower microRNA-193 and microRNA-331-5p content, microRNAs implicated in inhibiting osteogenesis and leukemic cell expansion respectively, compared to HFD-SED EVs. The results identify alterations in EV cargo as a novel mechanism by which exercise training alters stress hematopoiesis and the bone marrow niche.

Cathepsin B and Muscular Strength are Independently Associated with Cognitive Control.

Although muscular strength has been linked to greater cognitive function across different cognitive domains, the mechanism(s) through which this occurs remain(s) poorly understood. Indeed, while an emerging body of literature suggests peripheral myokines released from muscular contractions may play a role in this relationship, additional research is needed to understand this link. Accordingly, this study sought to compare the influences of a particular myokine, Cathepsin B (CTSB), and muscular strength on hippocampal-dependent relational memory and cognitive control in 40 adults (age = 50.0±7.3 yrs). Overnight fasted venous blood draws were taken to assess plasma CTSB and muscular strength was assessed as maximal isokinetic strength testing using a Biodex dynamometer. Cognitive performance was assessed using a Spatial Reconstruction Task to assess relational memory and a modified Flanker task to assess cognitive control. Neuroelectric function for cognitive control was assessed using event-related potentials (ERPs) recorded during the Flanker task. Initial bivariate correlational analyses revealed that neither sex, age, lean body mass, or muscular strength was associated with CTSB. However, CTSB was inversely associated with reaction time and fractional peak latency of the P3 component of the Flanker task. Muscular strength was also inversely associated with reaction time and positively associated with relational memory performance. However, the influence of muscular strength on relational memory did not persist following adjustment for covariates. Greater circulating CTSB was selectively associated with greater cognitive control as well as faster information processing speed. These findings are the first to link circulating CTSB to both cognitive control and neuroelectric function. Future intervention studies are needed to examine the effects of changes in muscular strength, circulating myokines, and different domains of cognitive function.

Muscle injury induces a transient senescence-like state that is required for myofiber growth during muscle regeneration.

Cellular senescence is the irreversible arrest of normally dividing cells and is driven by the cell cycle inhibitors Cdkn2a, Cdkn1a, and Trp53. Senescent cells are implicated in chronic diseases and tissue repair through their increased secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Here, we use spatial transcriptomics and single-cell RNA sequencing (scRNAseq) to demonstrate that cells displaying senescent characteristics are "transiently" present within regenerating skeletal muscle and within the muscles of D2-mdx mice, a model of Muscular Dystrophy. Following injury, multiple cell types including macrophages and fibrog-adipogenic progenitors (FAPs) upregulate senescent features such as senescence pathway genes, SASP factors, and senescence-associated beta-gal (SA-ß-gal) activity. Importantly, when these cells were removed with ABT-263, a senolytic compound, satellite cells are reduced, and muscle fibers were impaired in growth and myonuclear accretion. These results highlight that an "acute" senescent phenotype facilitates regeneration similar to skin and neonatal myocardium.

How Does Lifestyle Affect Hematopoiesis and the Bone Marrow Microenvironment?

Lifestyle factors are modifiable behavioral factors that have a significant impact on health and longevity. Diet-induced obesity and physical activity/exercise are two prevalent lifestyle factors that have strong relationships to overall health. The mechanisms linking obesity to negative health outcomes and the mechanisms linking increased participation in physical activity/exercise to positive health outcomes are beginning to be elucidated. Chronic inflammation, due in part to overproduction of myeloid cells from hematopoietic stem cells (HSCs) in the bone marrow, is an established mechanism responsible for the negative health effects of obesity. Recent work has shown that exercise training can reverse the aberrant myelopoiesis present in obesity in part by restoring the bone marrow microenvironment. Specifically, exercise training reduces marrow adipose tissue, increases HSC retention factor expression, and reduces pro-inflammatory cytokine levels in the bone marrow. Other, novel mechanistic factors responsible for these exercise-induced effects, including intercellular communication using extracellular vesicles (EVs), is beginning to be explored. This review will summarize the recent literature describing the effects of exercise on hematopoiesis in individuals with obesity and introduce the potential contribution of EVs to this process.

Creatine Monohydrate Supplementation, but not Creatyl-L-Leucine, Increased Muscle Creatine Content in Healthy Young Adults: A Double-Blind Randomized Controlled Trial.

Creatine (Cr) supplementation is a well-established strategy to enhance gains in strength, lean body mass, and power from a period of resistance training. However, the effectiveness of creatyl-L-leucine (CLL), a purported Cr amide, is unknown. Therefore, the purpose of this study was to assess the effects of CLL on muscle Cr content. Twenty-nine healthy men (n = 17) and women (n = 12) consumed 5 g/day of either Cr monohydrate (n = 8; 28.5 ± 7.3 years, 172.1 ± 11.0 cm, 76.6 ± 10.7 kg), CLL (n = 11; 29.2 ± 9.3 years, 170.3 ± 10.5 cm, 71.9 ± 14.5 kg), or placebo (n = 10; 30.3 ± 6.9 years, 167.8 ± 9.9 cm, 69.9 ± 11.1 kg) for 14 days in a randomized, double-blind design. Participants completed three bouts of supervised resistance exercise per week. Muscle biopsies were collected before and after the intervention for quantification of muscle Cr. Cr monohydrate supplementation which significantly increased muscle Cr content with 14 days of supplementation. No changes in muscle Cr were observed for the placebo or CLL groups. Cr monohydrate supplementation is an effective strategy to augment muscle Cr content while CLL is not.

The role of L-type amino acid transporter 1 (Slc7a5) during in vitro myogenesis.

Satellite cells are required for muscle regeneration, remodeling, and repair through their activation, proliferation, and differentiation; however, how dietary factors regulate this process remains poorly understood. The L-type amino acid transporter 1 (LAT1) transports amino acids, such as leucine, into mature myofibers, which then stimulate protein synthesis and anabolic signaling. However, whether LAT1 is expressed on myoblasts and is involved in regulating myogenesis is unknown. The aim of this study was to characterize the expressional and functional relevance of LAT1 during different stages of myogenesis and in response to growth and atrophic conditions in vitro. We determined that LAT1 is expressed by C2C12 and human primary myoblasts, and its gene expression is lower during differentiation (P < 0.05). Pharmacological inhibition and genetic knockdown of LAT1 impaired myoblast viability, differentiation, and fusion (all P < 0.05). LAT1 protein content in C2C12 myoblasts was not significantly altered in response to different leucine concentrations in cell culture media or in two in vitro atrophy models. However, LAT1 content was decreased in myotubes under atrophic conditions in vitro (P < 0.05). These findings indicate that LAT1 is stable throughout myogenesis and in response to several in vitro conditions that induce muscle remodeling. Further, amino acid transport through LAT1 is required for normal myogenesis in vitro.

Nutritional Regulation of Muscle Stem Cells in Exercise and Disease: The Role of Protein and Amino Acid Dietary Supplementation.

Human skeletal muscle is a remarkedly plastic tissue that has a high capacity to adapt in response to various stimuli. These adaptations are due in part to the function of muscle-resident stem/progenitor cells. Skeletal muscle regeneration and adaptation is facilitated by the activation and expansion of muscle stem cells (MuSCs). MuSC fate is regulated by signals released from cells in their niche, such as fibro-adipogenic progenitors (FAPs), as well as a variety of non-cellular niche components. Sufficient dietary protein consumption is critical for maximizing skeletal muscle adaptation to exercise and maintaining skeletal muscle in disease; however, the role of dietary protein in altering MuSC and FAP responses to exercise in healthy populations and skeletal muscle disease states requires more research. The present review provides an overview of this emerging field and suggestions for future directions. The current literature suggests that in response to resistance exercise, protein supplementation has been shown to increase MuSC content and the MuSC response to acute exercise. Similarly, protein supplementation augments the increase in MuSC content following resistance training. Endurance exercise, conversely, is an area of research that is sparse with respect to the interaction of protein supplementation and exercise on muscle stem/progenitor cell fate. Initial evidence suggests that protein supplementation augments the early myogenic response to acute endurance exercise but does not enhance the MuSC response to endurance training. Resistance training increases the number of proliferating FAPs with no additional effect of protein supplementation. Future research should continue to focus on the nutritional regulation of skeletal muscle stem/progenitor cell fate paired with studies examining the effects of exercise on a variety of human populations.

Muscle strength after resistance training correlates to mediators of muscle mass and mitochondrial respiration in middle-aged adults.

Skeletal muscle aging is a multidimensional pathology of atrophy, reduced strength, and oxidative damage. Although some molecular targets may mediate both hypertrophic and oxidative adaptations in muscle, their responsiveness in humans and relationship with functional outcomes like strength remain unclear. Promising therapeutic targets to combat muscle aging like apelin, vitamin D receptor (VDR), and spermine oxidase (SMOX) have been investigated in preclinical models but the adaptive response in humans is not well defined. In an exploratory investigation, we examined how strength gains with resistance training relate to regulators of both muscle mass and oxidative function in middle-aged adults. Forty-one middle-aged adults [18 male (M), 23 female (F); 50 ± 7 yr; 27.8 ± 3.7 kg/m2; means ± SD] participated in a 10-wk resistance training intervention. Muscle biopsies and plasma were sampled at baseline and postintervention. High-resolution fluo-respirometry was performed on a subset of muscle tissue. Apelin signaling (plasma apelin, P = 0.002; Apln mRNA, P < 0.001; apelin receptor mRNA Aplnr, P = 0.001) increased with resistance training. Muscle Vdr mRNA (P = 0.007) and Smox mRNA (P = 0.027) were also upregulated after the intervention. Mitochondrial respiratory capacity increased (Vmax, oxidative phosphorylation, and uncoupled electron transport system, P < 0.050), yet there were no changes in ADP sensitivity (Km P = 0.579), hydrogen peroxide emission (P = 0.469), nor transcriptional signals for mitochondrial biogenesis (nuclear respiratory factor 2, Gapba P = 0.766) and mitofusion (mitochondrial dynamin-like GTPase, Opa1 P = 0.072). Muscular strength with resistance training positively correlated to Apln, Aplnr, Vdr, and Smox transcriptional adaptations, as well as mitochondrial respiratory capacity (unadjusted P < 0.050, r = 0.400-0.781). Further research is required to understand the interrelationships of these targets with aged muscle phenotype.NEW & NOTEWORTHY Although some therapeutic targets may ameliorate hypertrophic and oxidative dysfunction with muscle aging in preclinical models, their responsiveness in human muscle remains unclear. We demonstrated that resistance training concurrently upregulated therapeutic targets of muscle aging and mitochondrial respiratory capacity, which positively correlated to strength gains. Specifically, we are the first to demonstrate that apelin and spermine oxidase are upregulated with resistance training in humans. Our work corroborates preclinical observations, with future work required for clinical efficacy.

Associations of the BDNF Val66Met Polymorphism With Body Composition, Cardiometabolic Risk Factors, and Energy Intake in Youth With Obesity: Findings From the HEARTY Study.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is functionally related to BDNF, and is associated with obesity and metabolic complications in adults, but limited research exists among adolescents. This study comparatively examined carriers and non-carriers of the BDNF Val66Met polymorphism on body composition, energy intake, and cardiometabolic profile among adolescents with obesity. The sample consisted of 187 adolescents with obesity; 99 were carriers of the homozygous Val (G/G) alleles and 88 were carriers of the Val/Met (G/A) or Met (A/A) alleles. Cardiometabolic profile and DNA were quantified from fasted blood samples. Body composition was assessed by magnetic resonance imaging (MRI). Compared to carriers of the homozygous Val (G/G) allele, carriers of the Val/Met (G/A) or Met/Met (A/A) variants exhibited significantly higher protein (p = 0.01) and fat (p = 0.05) intake, C-Reactive protein (p = 0.05), and a trend toward higher overall energy intake (p = 0.07), fat-free mass (p = 0.07), and lower HDL-C (p = 0.07) Results showed for the first time that among youth with obesity, carriers of the Val66Met BDNF Met-alleles exhibited significantly higher C-reactive protein and energy intake in the form of fat and protein compared to Val-allele carriers, thereby providing support for the possible role of BDNF in appetite, weight, and metabolic regulation during adolescence. Clinical Trial Registration: http://clinicaltrials.gov/, identifier NCT00195858.

Impact of Exercise Training on Hematological Outcomes Following Hematopoietic Cell Transplantation: A Scoping Review.

PURPOSE: Hematopoietic cell transplantation (HCT) is associated with significant risk prior to hematopoietic engraftment. Endurance exercise can modify the bone marrow microenvironment, alter hematopoiesis and accelerate hematopoietic regeneration in mouse models of transplantation. METHODS: A systematic review was conducted to clarify the impact of exercise on clinically relevant hemato-logical outcomes in patients following HCT. RESULTS: A systematic search of the literature identified 13 studies (total of 615 participants; 313 in study arms). Studies included exercise regimens that were primarily low-to-moderate intensity. A total of five studies re-ported on engraftment and length of stay, which were largely unchanged with intervention. Rates of graft-ver-sus host disease were reported in six studies whereas red cell and platelet transfusion needs were reported in four studies, neither of which was different with exercise. Survival was reported in four studies and was significantly improved by exercise in one study. CONCLUSIONS: Exercise in patients receiving HCT appears feasible and safe. Heterogeneity in type and intensity of exercise was observed and few studies examined high intensity exercise. Outcome reporting was inconsis-tent regarding transplant-related outcomes. Standardized hematological outcome measures are needed to clarify the impact of higher intensity exercise on HCT.

Exercise Improves Cancer-free Survival and Health Span in a Model of Radiation-induced Cancer.

INTRODUCTION: Radiation therapy increases the risk of secondary malignancy and morbidity in cancer survivors. The role of obesity and exercise training in modulating this risk is not well understood. As such, we used a preclinical model of radiation-induced malignancy to investigate whether diet-induced obesity and/or endurance exercise training altered lifelong survival, cancer incidence, and morbidity. METHODS: Male CBA mice were randomly divided into control diet/sedentary group (CTRL/SED), high-fat diet (45% fat)/sedentary group (HFD/SED), control diet/exercise group (2-3 d·wk-1; CTRL/EX), or high-fat diet/exercise group (HFD/EX) groups then exposed to whole-body radiation (3 Gy). End point monitoring and pathology determined mortality and cancer incidence, respectively. Health span index, a measure of morbidity, was determined by a composite measure of 10 anthropometric, metabolic, performance, and behavioral measures. RESULTS: Overall survival was higher in HFD/SED compared with CTRL/SED (P < 0.05). The risk of cancer-related mortality by 18 months postradiation was 1.99 and 1.63 in HFD/SED compared with CTRL/EX (RR = 1.99, 95% confidence interval = 1.20-3.31, P = 0.0081) and CTRL/SED (RR = 1.63, 95% confidence interval = 1.06-2.49, P = 0.0250), respectively. The number of mice at end point with cancer was higher in HFD/SED compared with CTRL/EX and CTRL/SED (P < 0.05). Health span index was highest in CTRL/EX (score = +2.5), followed by HFD/EX (score = +1), and HFD/SED (score = -1) relative to CTRL/SED. CONCLUSION: This work provides the basis for future preclinical studies investigating the dose-response relationship between exercise training and late effects of radiation therapy as well as the mechanisms responsible for these effects.

Higher protein intake during resistance training does not potentiate strength, but modulates gut microbiota, in middle-aged adults: a randomized control trial.

Protein intake above the recommended dietary allowance (RDA) and resistance training are known anabolic stimuli to support healthy aging. Specifically, protein supplementation after resistance exercise and nightly are strategies to maximize utilization of protein intake above the RDA in healthy adults. As such, the primary objective was to examine the efficacy of protein supplementation and nutritional counseling resulting in either moderate (MOD: ∼1.0 g·kg-1·day-1) or higher (HIGH: ∼1.6 g·kg-1·day-1) protein intake during resistance training on strength (one-repetition maximum, 1-RM; isokinetic and isometric peak torque) in healthy middle-aged adults. Exploratory analyses include diet-exercise effects on lean body mass (LBM), clinical biomarkers, gut microbiota, and diet composition. In all, 50 middle-aged adults (age: 50 ± 8 yr, BMI: 27.2 ± 4.1 kg/m2) were randomized to either MOD or HIGH protein intake during a 10-wk resistance training program (3 × wk). Participants received dietary counseling and consumed either 15 g (MOD) or 30 g (HIGH) of protein from lean beef in the immediate postexercise period and each evening. Maximal strength (1-RM) for all upper and lower body exercises significantly increased with no effect of protein intake (P < 0.050). There was a main effect of time for LBM (P < 0.005). Cardiovascular, renal, or glycemic biomarkers were not affected by the intervention. Gut microbiota were associated with several health outcomes (P < 0.050). In conclusion, higher protein intake above moderate amounts does not potentiate resistance training adaptations in previously untrained middle-aged adults. This trial was registered at clinicaltrials.gov as NCT03029975.NEW & NOTEWORTHY Our research evaluates the efficacy of higher in comparison with moderate animal-based protein intake on resistance exercise training-induced muscle strength, clinical biomarkers, and gut microbiota in middle-aged adults through a dietary counseling-controlled intervention. Higher protein intake did not potentiate training adaptations, nor did the intervention effect disease biomarkers. Both diet and exercise modified gut microbiota composition. Collectively, moderate amounts of high-quality, animal-based protein is sufficient to promote resistance exercise adaptations at the onset of aging.

No association between dopaminergic polymorphisms and response to treatment of binge-eating disorder.

BACKGROUND: The genetics of binge-eating disorder (BED) is an emerging topic, with dopaminergic genes being implicated in its etiology due to the role that dopamine (DA) plays in food reward sensitivity and self-regulation of eating behavior. However, no study to date has examined if DA genes influence response to behavioral treatment of BED. OBJECTIVE: The primary objective of this study was to examine the ability of DA-associated polymorphisms to predict BED treatment response measured using binge frequency over 12 months. As secondary objectives, this study examined cross-sectional relationships between these polymorphisms and anthropometrics in women living with and without BED and obesity. METHODS: Women aged 18-64 years old were genotyped for the DA-related SNPs DRD2/ANKK1 Taq1A (rs1800497) and COMT (rs4680), as well as the DA-related uVNTRs DAT-1 (SLC6A3) and MAO-A. A multi-locus DA composite score was formed from these 4 polymorphisms using genotypes known to have a functional impact resulting in modified DA signaling. Binge frequency (Eating Disorder Examination - Interview) and body composition (Tanita BC-418) were assessed in a pre-post analysis to examine genetic predictors of treatment response in women living with obesity and BED. Secondary data analysis was conducted on a cross-sectional comparison of three groups of women enrolled in trial group treatment for BED: women living with obesity and BED (n = 72), obesity without BED (n = 27), and normal-weight without BED (n = 45). RESULTS: There were no significant genotype × time interactions related to anthropometrics or binge frequency for any individual DA genotypes, or to the composite score reflecting DA availability. At baseline, there were no significant between-group differences in frequencies of DA-related alleles, nor were there associations between genotypes and anthropometrics. CONCLUSIONS: Our study found no evidence to suggest that the DRD2/ANKK1 Taq1A, COMT, MAO-A, or DAT-1 polymorphisms are associated with response to behavioral intervention for BED as measured by changes in binge frequency. Future studies should examine a greater variety of dopaminergic polymorphisms, other candidate genes that target other neurotransmitter systems, as well as examine their impact on both behavioral and pharmacological-based treatment for BED.