Low Response to Aerobic Training in Metabolic Disease: Role of Skeletal Muscle.

Aerobic exercise is established to increase cardiorespiratory fitness (CRF), which is linked to reduced morbidity and mortality. However, people with metabolic diseases such as type 1 and type 2 diabetes may be more likely to display blunted improvements in CRF with training. Here, we present evidence supporting the hypothesis that altered skeletal muscle signaling and remodeling may contribute to low CRF with metabolic disease.

ROAR ED-SANE: A Retrospective Observational Assessment Review of an Emergency Department Sexual Assault Nurse Examiner Program's Adherence to Centers for Disease Control and Prevention Guidelines for Sexually Transmitted Infections.

BACKGROUND: Sexual assault survivors are at increased risk for sexually transmitted infections. Sexual Assault Nurse Examiner programs guide sexually transmitted infection treatment, monitoring, and follow-up scheduling according to guidelines by the Centers for Disease Control and Prevention (CDC). Reported low rates of provider adherence to CDC treatment guidelines and patient adherence to follow-up necessitate a review of medication prescribing and follow-up scheduling practices, especially at smaller community hospitals in the United States. METHODS: A retrospective medical record review was conducted to assess adherence rates to CDC guidelines for prescribing practices, scheduling, and follow-up of sexual assault survivors. We included pediatric and adult patients presenting to the emergency department (ED) and participating in the ED Sexual Assault Nurse Examiner program at a rural, community-based teaching hospital in La Crosse, WI, from January 2018 to December 2021. Descriptive statistics were used to evaluate results. RESULTS: Analysis included 103 patients. Prescribing adherence to CDC guidelines was >80% for all except human immunodeficiency virus (53.4%), trichomoniasis (68.1%), and hepatitis B (69%). Of the 38 patients who had a follow-up scheduled during their ED encounter, 78.9% attended their scheduled follow-up and 94.7% of those appointments were scheduled within the CDC-recommended time frame, leading to an overall adherence of 40%. CONCLUSIONS: Adherence rates were high for most prescribing practices, and attendance of scheduled follow-up was higher than expected. Opportunities to improved adherence to CDC guidelines were identified in prescribing for 3 disease states (human immunodeficiency virus, trichomoniasis, and hepatitis B) and in scheduling of follow-up.

Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle.

NEW FINDINGS: What is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus. ABSTRACT: Divergent skeletal muscle phenotypes result from chronic resistance-type versus endurance-type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non-overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. -6 ± 18%, mean ± SD, P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between-group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.

Effect of ß-Lactam Plus Macrolide Versus Fluoroquinolone on 30-Day Readmissions for Community-Acquired Pneumonia.

BACKGROUND: Antibiotic therapy with a macrolide and ß-lactam or a fluoroquinolone for the empirical treatment of community-acquired pneumonia (CAP) in an inpatient non-intensive care setting is recommended per guidelines. Studies show that these treatments have similar outcomes, including death, adverse effects, and bacterial eradication. However, a comparison of 30-day readmission rates between these treatments is limited. STUDY QUESTION: To determine whether 30-day readmissions for patients treated for CAP in a regional hospital differed between a fluoroquinolone monotherapy and a ß-lactam plus macrolide combination therapy. STUDY DESIGN: Retrospective cohort study of patients aged ≥18 years with a CAP diagnosis who were admitted to the same regional hospital from December 1, 2011, through December 1, 2016. MEASURES AND OUTCOMES: Patients receiving a third-generation cephalosporin plus macrolide were compared with those receiving a respiratory fluoroquinolone. Exclusion criteria were concurrent or recent use of the study antibiotics; death, transfer, or transition to hospice; and diagnosis of hospital-acquired pneumonia or health care-associated pneumonia. The collected data were 30-day readmission rates, antibiotic regimens, demographic characteristics, and pneumonia severity index and comorbidity scores. Association between treatment group and readmissions was assessed with logistic regression. Association between readmissions and individual data points between the 2 treatment groups was calculated with multivariate regression and odds ratio (95% confidence interval). RESULTS: Of 432 patients, 171 met inclusion criteria (fluoroquinolone group, n = 101; ß-lactam plus macrolide group, n = 70). Thirty-day readmissions were not significantly different between the fluoroquinolone group and ß-lactam plus macrolide group (P = 0.58). Increased 30-day readmissions were independently associated with male sex and hospital length of stay (P < 0.05). Length of stay was approximately 3 days and did not differ between treatment groups. CONCLUSIONS: No difference was seen in 30-day readmissions between CAP patients who received fluoroquinolone monotherapy and those who received ß-lactam plus macrolide combination therapy.

Sucrose nonfermenting AMPK-related kinase (SNARK) regulates exercise-stimulated and ischemia-stimulated glucose transport in the heart.

The signaling mechanisms mediating myocardial glucose transport are not fully understood. Sucrose nonfermenting AMP-activated protein kinase (AMPK)-related kinase (SNARK) is an AMPK-related protein kinase that is expressed in the heart and has been implicated in contraction-stimulated glucose transport in mouse skeletal muscle. We first determined if SNARK is phosphorylated on Thr208 , a site critical for SNARK activity. Mice were treated with exercise, ischemia, submaximal insulin, or maximal insulin. Treadmill exercise slightly, but significantly increased SNARK Thr208 phosphorylation. Ischemia also increased SNARK Thr208 phosphorylation, but there was no effect of submaximal or maximal insulin. HL1 cardiomyocytes were used to overexpress wild-type (WT) SNARK and to knockdown endogenous SNARK. Overexpression of WT SNARK had no effect on ischemia-stimulated glucose transport; however, SNARK knockdown significantly decreased ischemia-stimulated glucose transport. SNARK overexpression or knockdown did not alter insulin-stimulated glucose transport or glycogen concentrations. To study SNARK function in vivo, SNARK heterozygous knockout mice (SNARK+/- ) and WT littermates performed treadmill exercise. Exercise-stimulated glucose transport was decreased by ~50% in hearts from SNARK+/- mice. In summary, exercise and ischemia increase SNARK Thr208 phosphorylation in the heart and SNARK regulates exercise-stimulated and ischemia-stimulated glucose transport. SNARK is a novel mediator of insulin-independent glucose transport in the heart.

Perceptions and practices of mosquito-borne diseases in Alabama - is concern where it should be?

BACKGROUND: The Gulf Coast of the United States is home to mosquito vectors that may spread disease causing pathogens, and environmental conditions that are ideal for the sustained transmission of mosquito-borne pathogens. Understanding public perceptions of mosquito-borne diseases and mosquito prevention strategies is critical for the development of effective vector control strategies and public health interventions. Here, we present a survey conducted in Mobile, Alabama along the Gulf Coast to better understand public perceptions of mosquito-borne diseases, mosquito control activities, and potential risk factors. METHODS: Using Knowledge, Attitude, and Practice (KAPs) assessments, we surveyed populations living in 12 zip codes in Mobile, Alabama using a 7-point Likert scale and frequency assessments. Survey participants were asked about vector control efforts, knowledge of mosquito-borne diseases, and understanding of mosquito ecology and breeding habitats. RESULTS: One hundred twenty-six surveys were completed in Mobile, Alabama, revealing that 73% of participants reported being bitten by a mosquito in the last 30 days and mosquitoes were frequently seen in their homes. Ninety-four percent of respondents had heard of Zika Virus at the time of the survey, and respondents reported being least familiar with dengue virus and chikungunya virus. CONCLUSIONS: Chikungunya virus, dengue virus, malaria, West Nile virus, and Zika virus have been documented in the Gulf Coast of the United States. The mosquitoes which vector all of these diseases are presently in the Gulf Coast meaning all five diseases pose a potential risk to human health. The results of this survey emphasize knowledge gaps that public health officials can address to empower the population to reduce their risk of these mosquito-borne diseases. Each species of mosquito has specific preferences for breeding and feeding and there is no one size fits all prevention approach, educating people on the need for a variety of approaches in order to address all species will further empower them to control mosquitoes where they live and further reduce their risk of disease.

Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling.

Older individuals have a reduced capacity to induce muscle hypertrophy with resistance exercise (RE), which may contribute to the age-induced loss of muscle mass and function, sarcopenia. We tested the novel hypothesis that dysregulation of microRNAs (miRNAs) may contribute to reduced muscle plasticity with aging. Skeletal muscle expression profiling of protein-coding genes and miRNA was performed in younger (YNG) and older (OLD) men after an acute bout of RE. 21 miRNAs were altered by RE in YNG men, while no RE-induced changes in miRNA expression were observed in OLD men. This striking absence in miRNA regulation in OLD men was associated with blunted transcription of mRNAs, with only 42 genes altered in OLD men vs. 175 in YNG men following RE, demonstrating a reduced adaptability of aging muscle to exercise. Integrated bioinformatics analysis identified miR-126 as an important regulator of the transcriptional response to exercise and reduced lean mass in OLD men. Manipulation of miR-126 levels in myocytes, in vitro, revealed its direct effects on the expression of regulators of skeletal muscle growth and activation of insulin growth factor 1 (IGF-1) signaling. This work identifies a mechanistic role of miRNA in the adaptation of muscle to anabolic stimulation and reveals a significant impairment in exercise-induced miRNA/mRNA regulation with aging.

Overexpression of TRB3 in muscle alters muscle fiber type and improves exercise capacity in mice.

Increasing evidence suggests that TRB3, a mammalian homolog of Drosophila tribbles, plays an important role in cell growth, differentiation, and metabolism. In the liver, TRB3 binds and inhibits Akt activity, whereas in adipocytes, TRB3 upregulates fatty acid oxidation. In cultured muscle cells, TRB3 has been identified as a potential regulator of insulin signaling. However, little is known about the function and regulation of TRB3 in skeletal muscle in vivo. In the current study, we found that 4 wk of voluntary wheel running (6.6 ± 0.4 km/day) increased TRB3 mRNA by 1.6-fold and protein by 2.5-fold in the triceps muscle. Consistent with this finding, muscle-specific transgenic mice that overexpress TRB3 (TG) had a pronounced increase in exercise capacity compared with wild-type (WT) littermates (TG: 1,535 ± 283; WT: 644 ± 67 joules). The increase in exercise capacity in TRB3 TG mice was not associated with changes in glucose uptake or glycogen levels; however, these mice displayed a dramatic shift toward a more oxidative/fatigue-resistant (type I/IIA) muscle fiber type, including threefold more type I fibers in soleus muscles. Skeletal muscle from TRB3 TG mice had significantly decreased PPARα expression, twofold higher levels of miR208b and miR499, and corresponding increases in the myosin heavy chain isoforms Myh7 and Myb7b, which encode these microRNAs. These findings suggest that TRB3 regulates muscle fiber type via a peroxisome proliferator-activated receptor-α (PPAR-α)-regulated miR499/miR208b pathway, revealing a novel function for TRB3 in the regulation of skeletal muscle fiber type and exercise capacity.

Cardiorespiratory fitness, body composition, diabetes, and longevity: a two-sample Mendelian randomization study.

CONTEXT: Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality. OBJECTIVE: We investigated the causality and directionality of the associations of VO2max with body composition, physical activity, diabetes, performance enhancers, and longevity. METHODS: Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional two-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO2max) was estimated from a submaximal cycle ramp test (N≈90,000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg). RESULTS: Genetically predicted higher (per one standard deviation increase) body fat percentage was associated with lower VO2max (ß=-0.36 [95% CI: -0.40, -0.32], p=6E-77). Meanwhile, genetically predicted higher appendicular lean mass (0.10 [0.08,0.13] p=3E-16), physical activity (0.29 [0.07,0.52]), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (p<0.01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max showed no associations. CONCLUSION: Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO2max is not causally associated with T2D or longevity.

Enhancing Sepsis Outcomes: A 7-Year Multidisciplinary Endeavor.

Regulatory bodies in the United States have implemented quality metrics aimed at improving outcomes for patients with severe sepsis and septic shock. The current study was a quality improvement (QI) project in a community-based academic center aimed at improving adherence to sepsis quality metrics, time to antibiotic administration, and patient outcomes. Electronic health record systems were utilized to capture sepsis-related data. Regular audits and feedback sessions were conducted to identify areas for improvement, with a focus on the timely administration of antibiotics. Interventions included improving access to antibiotics, transitioning from intravenous piggyback to intravenous push formulations, and providing continuous staff education and training. This multidisciplinary QI initiative led to significant improvements in the mortality index, length of stay index, and direct cost index for patients with sepsis. Targeted multidisciplinary QI interventions resulted in improved quality metrics and patient outcomes.

Cardiorespiratory Fitness Is Impaired in Type 1 and Type 2 Diabetes: A Systematic Review, Meta-Analysis, and Meta-Regression.

INTRODUCTION: Low cardiorespiratory fitness (CRF) increases the risk of cardiovascular disease by up to 8-fold, and is one of the strongest predictors of mortality. Some studies demonstrate impaired CRF in people living with type 1 and type 2 diabetes compared to those without diabetes, while others demonstrate no diabetes-associated impairment in CRF. PURPOSE: We aimed to determine whether diabetes can influence CRF, and if so, identify clinical associations underlying diabetes-associated exercise impairments. METHODS: 68 studies were included in the quantitative analysis. Standardized mean difference (SMD) was calculated and meta-analyses and meta-regressions were performed by using a random-effects model. RESULTS: Diabetes is associated with a large negative effect on CRF (SMD = -0.80; p < 0.001)- an effect that is partially mitigated, but still significant, in those with high physical activity levels (SMD = -0.50; p = 0.007). A sedentary lifestyle (SMD = -0.83; p = 0.007), and the presence of clinical complications related to diabetes (SMD = -1.66; p < 0.001) predict a greater magnitude of CRF reduction in people with diabetes compared to controls without diabetes. Both type 1 and type 2 diabetes are independently associated with impaired CRF compared to controls without diabetes; however, the effect is significantly greater in those type 2 diabetes (SMD = -0.97; p < 0.001). Meta-regression analysis demonstrates the effects of diabetes on CRF are primarily associated with HbA1c levels for type 1 diabetes (B = -0.07; p < 0.001) and body mass index for type 2 diabetes (B = -0.17; p = 0.005). CONCLUSIONS: These data demonstrate a negative influence of diabetes on the key risk factor of low CRF and provide critical insight into specific clinical markers of low CRF associated with diabetes.

Exercise training enhances white adipose tissue metabolism in rats selectively bred for low- or high-endurance running capacity.

Impaired visceral white adipose tissue (WAT) metabolism has been implicated in the pathogenesis of several lifestyle-related disease states, with diminished expression of several WAT mitochondrial genes reported in both insulin-resistant humans and rodents. We have used rat models selectively bred for low- (LCR) or high-intrinsic running capacity (HCR) that present simultaneously with divergent metabolic phenotypes to test the hypothesis that oxidative enzyme expression is reduced in epididymal WAT from LCR animals. Based on this assumption, we further hypothesized that short-term exercise training (6 wk of treadmill running) would ameliorate this deficit. Approximately 22-wk-old rats (generation 22) were studied. In untrained rats, the abundance of mitochondrial respiratory complexes I-V, citrate synthase (CS), and PGC-1 was similar for both phenotypes, although CS activity was greater than 50% in HCR (P = 0.09). Exercise training increased CS activity in both phenotypes but did not alter mitochondrial protein content. Training increased the expression and phosphorylation of proteins with roles in ß-adrenergic signaling, including ß3-adrenergic receptor (16% increase in LCR; P < 0.05), NOR1 (24% decrease in LCR, 21% decrease in HCR; P < 0.05), phospho-ATGL (25% increase in HCR; P < 0.05), perilipin (25% increase in HCR; P < 0.05), CGI-58 (15% increase in LCR; P < 0.05), and GLUT4 (16% increase in HCR; P < 0.0001). A training effect was also observed for phospho-p38 MAPK (12% decrease in LCR, 20% decrease in HCR; P < 0.05) and phospho-JNK (29% increase in LCR, 20% increase in HCR; P < 0.05). We conclude that in the LCR-HCR model system, mitochondrial protein expression in WAT is not affected by intrinsic running capacity or exercise training. However, training does induce alterations in the activity and expression of several proteins that are essential to the intracellular regulation of WAT metabolism.

Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function.

Rats selectively bred for low (LCR) or high (HCR) intrinsic running capacity simultaneously present with contrasting risk factors for cardiovascular and metabolic disease. However, the impact of these phenotypes on left ventricular (LV) morphology and microvascular function, and their progression with aging, remains unresolved. We tested the hypothesis that the LCR phenotype induces progressive age-dependent LV remodeling and impairments in microvascular function, glucose utilization, and ß-adrenergic responsiveness, compared with HCR. Hearts and vessels isolated from female LCR (n = 22) or HCR (n = 26) were studied at 12 and 35 wk. Nonselected N:NIH founder rats (11 wk) were also investigated (n = 12). LCR had impaired glucose tolerance and elevated plasma insulin (but not glucose) and body-mass at 12 wk compared with HCR, with early LV remodeling. By 35 wk, LV prohypertrophic and glucose transporter GLUT4 gene expression were up- and downregulated, respectively. No differences in LV ß-adrenoceptor expression or cAMP content between phenotypes were observed. Macrovascular endothelial function was predominantly nitric oxide (NO)-mediated in both phenotypes and remained intact in LCR for both age-groups. In contrast, mesenteric arteries microvascular endothelial function, which was impaired in LCR rats regardless of age. At 35 wk, endothelial-derived hyperpolarizing factor-mediated relaxation was impaired whereas the NO contribution to relaxation is intact. Furthermore, there was reduced ß2-adrenoceptor responsiveness in both aorta and mesenteric LCR arteries. In conclusion, diminished intrinsic exercise capacity impairs systemic glucose tolerance and is accompanied by progressive development of LV remodeling. Impaired microvascular perfusion is a likely contributing factor to the cardiac phenotype.

Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle.

The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKalpha2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle.

Pharmacist adjustment of preoperative antibiotic orders to the preferred preoperative antibiotic cefazolin for patients with penicillin allergy labeling.

PURPOSE: Emerging literature has detailed the safe use of cefazolin in patients with immunoglobulin E-mediated penicillin allergy labeling (PAL) such as hives and anaphylaxis. The purpose of this article is to detail efforts led by an antimicrobial stewardship pharmacist working with an interdisciplinary team to optimize preoperative antimicrobials in patients with PAL. METHODS: A pharmacist-led, interdisciplinary collaborative practice agreement (CPA) was activated in January 2020 to permit pharmacists to independently optimize preoperative antibiotics to the preferred cefazolin in patients with PAL if nonsevere or severe reactions had been reported. A patient registry was established covering the timeframe between January 8, 2020, and January 6, 2022. Reaction during surgery was assessed via 2-provider documentation, which included surgeon and anesthesiology staff documentation of any complications during the procedure related to a suspected allergic safety event. Utilization of cefazolin, clindamycin, and vancomycin for preoperative prophylaxis was monitored before and after implementation of the CPA. RESULTS: During the stated timeframe, 10,182 procedures and/or surgeries were completed on 1,572 (15.4%) patients with PAL and 659 (41.9%) patients previously reporting at least one reaction categorized as a severe reaction, which was hives for 71.2% of these patients. Of the 659 patients with PAL reporting a severe reaction, 356 received a preoperative cephalosporin (cefazolin, 98.8%; ceftriaxone, 1.2%) and tolerated it without a reported safety event, including 52 patients with PAL previously reporting anaphylaxis. An increase in preferred preoperative antimicrobial prophylaxis utilization was noted (cefazolin: 86% to 96.3%, P < 0.001; 2019 to 2021) with reductions noted in the use of nonpreferred preoperative antibiotics (clindamycin: 2.1% to 0.2%, P < 0.001; vancomycin: 3.2% to 0.4%, P < 0.001; 2019 to 2021). CONCLUSION: A pharmacist-led, interdisciplinary CPA increased preferred preoperative antimicrobial use in patients with PAL reporting severe allergic reactions, including hives and anaphylaxis, without reported safety events.

Canagliflozin Prevents Hyperglycemia-Associated Muscle Extracellular Matrix Accumulation and Improves the Adaptive Response to Aerobic Exercise.

Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium-glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg/kg/day), could restore exercise training response in a model of hyperglycemia (low-dose streptozotocin [STZ]). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ-treated mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyperactivation of c-Jun N-terminal kinase (JNK)/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK/SMAD2 signaling with acute exercise was twofold higher in STZ compared with control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak, and impaired metabolic health (oral glucose tolerance test-derived insulin sensitivity). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by cotherapy with SGLT2i.

Effect of short-term hindlimb immobilization on skeletal muscle atrophy and the transcriptome in a low compared with high responder to endurance training model.

Skeletal muscle atrophy is a physiological response to disuse, aging, and disease. We compared changes in muscle mass and the transcriptome profile after short-term immobilization in a divergent model of high and low responders to endurance training to identify biological processes associated with the early atrophy response. Female rats selectively bred for high response to endurance training (HRT) and low response to endurance training (LRT; n = 6/group; generation 19) underwent 3 day hindlimb cast immobilization to compare atrophy of plantaris and soleus muscles with line-matched controls (n = 6/group). RNA sequencing was utilized to identify Gene Ontology Biological Processes with differential gene set enrichment. Aerobic training performed prior to the intervention showed HRT improved running distance (+60.6 ± 29.6%), while LRT were unchanged (-0.3 ± 13.3%). Soleus atrophy was greater in LRT vs. HRT (-9.0 ±8.8 vs. 6.2 ±8.2%; P<0.05) and there was a similar trend in plantaris (-16.4 ±5.6% vs. -8.5 ±7.4%; P = 0.064). A total of 140 and 118 biological processes were differentially enriched in plantaris and soleus muscles, respectively. Soleus muscle exhibited divergent LRT and HRT responses in processes including autophagy and immune response. In plantaris, processes associated with protein ubiquitination, as well as the atrogenes (Trim63 and Fbxo32), were more positively enriched in LRT. Overall, LRT demonstrate exacerbated atrophy compared to HRT, associated with differential gene enrichments of biological processes. This indicates that genetic factors that result in divergent adaptations to endurance exercise, may also regulate biological processes associated with short-term muscle unloading.

Exercise training reverses impaired skeletal muscle metabolism induced by artificial selection for low aerobic capacity.

We have used a novel model of genetically imparted endurance exercise capacity and metabolic health to study the genetic and environmental contributions to skeletal muscle glucose and lipid metabolism. We hypothesized that metabolic abnormalities associated with low intrinsic running capacity would be ameliorated by exercise training. Selective breeding for 22 generations resulted in rat models with a fivefold difference in intrinsic aerobic capacity. Low (LCR)- and high (HCR)-capacity runners remained sedentary (SED) or underwent 6 wk of exercise training (EXT). Insulin-stimulated glucose transport, insulin signal transduction, and rates of palmitate oxidation were lower in LCR SED vs. HCR SED (P < 0.05). Decreases in glucose and lipid metabolism were associated with decreased ß2-adrenergic receptor (ß2-AR), and reduced expression of Nur77 target proteins that are critical regulators of muscle glucose and lipid metabolism [uncoupling protein-3 (UCP3), fatty acid transporter (FAT)/CD36; P < 0.01 and P < 0.05, respectively]. EXT reversed the impairments to glucose and lipid metabolism observed in the skeletal muscle of LCR, while increasing the expression of ß2-AR, Nur77, GLUT4, UCP3, and FAT/CD36 (P < 0.05) in this tissue. However, no metabolic improvements were observed following exercise training in HCR. Our results demonstrate that metabolic impairments resulting from genetic factors (low intrinsic aerobic capacity) can be overcome by an environmental intervention (exercise training). Furthermore, we identify Nur77 as a potential mechanism for improved skeletal muscle metabolism in response to EXT.

Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle.

Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.

Effect of Pharmacist Audit on Antibiotic Duration for Pneumonia and Urinary Tract Infection.

OBJECTIVE: To assess the effect of clinical pharmacists in daily audits, under the direction of an antimicrobial stewardship program, of antibiotic treatment durations for the common inpatient disease states of community-acquired pneumonia (CAP) and urinary tract infection (UTI). PATIENTS AND METHODS: This was a retrospective single-center cohort study that evaluated the difference in the duration of antibiotic therapy for CAP or non-catheter-associated UTI of hospitalized patients who received a daily audit by clinical pharmacists compared with patients who did not receive a daily audit. Retrospective chart review included randomly selected hospitalized patients diagnosed with CAP or UTI during preaudit and postaudit periods. RESULTS: The preaudit group had 64 patients; and the postaudit group, 51 patients. The therapy duration was 7 days in the preaudit group and 6 days in the postaudit group (P=.55). Fluoroquinolone use was reduced in the postaudit group and was significantly less than in the preaudit group (24 [37.5%] vs 7 [13.7%]; P=.007). CONCLUSION: The daily audits of clinical pharmacists may be an effective method to reduce the duration of antibiotic therapy and are effective in the reduction of fluoroquinolone use. Additional studies must be done to further investigate the effects of clinical pharmacist antimicrobial stewardship efforts.