A Laing distal myopathy-associated proline substitution in the ß-myosin rod perturbs myosin cross-bridging activity.

Proline substitutions within the coiled-coil rod region of the ß-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin-myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractility and greater ATP consumption. Similarly, molecular analysis of muscle biopsies from patients with MPD1 revealed a significant increase in sarcomeric DRX content, as observed in a subset of myosin motor domain mutations causing hypertrophic cardiomyopathy. Finally, oral administration of MYK-581, a small molecule that decreases the population of heads in the DRX configuration, significantly improved the limited running capacity of the R1500P-transgenic mice and corrected the increased DRX state of the myofibrils from patients. These studies provide evidence of the molecular pathogenesis of proline rod mutations and lay the groundwork for the therapeutic advancement of myosin modulators.

Short-term high-intensity interval training improves fitness before surgery: A randomized clinical trial.

PURPOSE: Improving cardiopulmonary reserve, or peak oxygen consumption( V ˙ O2peak ), may reduce postoperative complications; however, this may be difficult to achieve between diagnosis and surgery. Our primary aim was to assess the efficacy of an approximate 14-session, preoperative high-intensity interval training(HIIT) program to increase V ˙ O2peak by a clinically relevant 2 ml·kg-1 ·min-1 . Our secondary aim was to document clinical outcomes. METHODOLOGY: In this prospective study, participants aged 45-85 undergoing major abdominal surgery were randomized to standard care or 14 sessions of HIIT over 4 weeks. HIIT sessions involved approximately 30 min of stationary cycling. Interval training alternated 1 min of high (with the goal of reaching 90% max heart rate at least once during the session) and low/moderate-intensity cycling. Cardiopulmonary exercise testing(CPET) measured the change in V ˙ O2peak from baseline to surgery. Clinical outcomes included postoperative complications, length of stay(LOS), and Short Form 36 quality of life questionnaire(SF-36). RESULTS: Of 63 participants, 46 completed both CPETs and 50 completed clinical follow-up. There was a significant improvement in the HIIT group's mean ± SD V ˙ O2peak (HIIT 2.87 ± 1.94 ml·kg1 ·min-1 vs standard care 0.15 ± 1.93, with an overall difference of 2.73 ml·kg1 ·min-1 95%CI [1.53, 3.93] p < 0.001). There were no statistically significant differences between groups for clinical outcomes, although the observed differences consistently favored the exercise group. This was most notable for total number of complications (0.64 v 1.16 per patient, p = 0.07), SF-36 physical component score (p = 0.06), and LOS (mean 5.5 v 7.4 days, p = 0.07). CONCLUSIONS: There was a significant improvement in V ˙ O2peak with a four-week preoperative HIIT program. Further appropriately powered work is required to explore the impact of preoperative HIIT on postoperative clinical outcomes.

Chronic Environmental or Genetic Elevation of Galanin in Noradrenergic Neurons Confers Stress Resilience in Mice.

The neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species specific. Moreover, use of intracerebroventricular (ICV) galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic wheel running) increases stress resilience and galanin expression in the LC of male and female mice. Next, we used transgenic mice that overexpress galanin in noradrenergic neurons (Gal OX) to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress. We found that three weeks of ad libitum access to a running wheel in their home cage increased galanin mRNA in the LC of mice, which was correlated with and conferred resilience to stress. The effects of exercise were phenocopied by galanin overexpression in noradrenergic neurons, and Gal OX mice were resistant to the anxiogenic effect of optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.SIGNIFICANCE STATEMENT Understanding the neurobiological mechanisms underlying behavioral responses to stress is necessary to improve treatments for stress-related neuropsychiatric disorders. Increased physical activity is associated with stress resilience in humans, but the neurobiological mechanisms underlying this effect are not clear. Here, we investigate a potential causal mechanism of this effect driven by the neuropeptide galanin from the main noradrenergic nucleus, the locus coeruleus (LC). We show that chronic voluntary wheel running in mice increases stress resilience and increases galanin expression in the LC. Furthermore, we show that genetic overexpression of galanin in noradrenergic neurons causes resilience to a stressor and the anxiogenic effects of optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.

HIIT Improves Left Ventricular Exercise Response in Adults with Type 2 Diabetes.

Type 2 diabetes is associated with reduced left ventricular reserve. It is unclear whether exercise training improves left ventricular function in people with type 2 diabetes. PURPOSE: This study aimed to determine whether 3 months of high-intensity interval training (HIIT) improves left ventricular function during exercise in adults with type 2 diabetes. METHODS: Participants performed a V˙O2peak test and received a DXA scan and total blood volume measurement at baseline. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular stroke volume (LVSV) were then measured at rest and during low- and moderate-intensity semirecumbent exercise in adults with type 2 diabetes before and after 3 months of HIIT (n = 11) or no training (control) (n = 5). The effects of HIIT were determined using repeated-measures ANOVA. RESULTS: HIIT increased V˙O2peak by approximately 15% (P < 0.002) but did not change body composition or total blood volume. LVESV decreased and LVEDV and LVSV increased from rest to moderate-intensity exercise in both groups at baseline (all P < 0.01). Three months of HIIT increased LVEDV (P = 0.008) and LVSV (P = 0.02) at all conditions, but there was no difference in controls (all P > 0.05). HIIT augmented the reduction in LVESV from rest to moderate-intensity exercise (P < 0.04), but LVESV was unchanged in controls. Increased LVEDV explained 51% of the change in LVSV after HIIT intervention. Mitral inflow parameters and mitral annular velocities were unaffected by HIIT (all P > 0.05). CONCLUSIONS: HIIT training increased the LVSV response to exercise in adults with type 2 diabetes. These data suggest that HIIT can improve LV filling and emptying during exercise and reverse early cardiac consequences of type 2 diabetes.

Protocol, and practical challenges, for a randomised controlled trial comparing the impact of high intensity interval training against standard care before major abdominal surgery: study protocol for a randomised controlled trial.

BACKGROUND: Risk factors, such as the number of pre-existing co-morbidities, the extent of the underlying pathology and the magnitude of the required operation, cannot be changed before surgery. It may, however, be possible to improve the cardiopulmonary fitness of the patient with an individualised exercise program. We are performing a randomised controlled trial (RCT) assessing the impact of High Intensity Interval Training (HIIT) on preoperative cardiopulmonary fitness and postoperative outcomes in patients undergoing major abdominal surgery. METHODS: Consecutive eligible patients undergoing elective abdominal surgery are being randomised to HIIT or standard care in a 1:1 ratio. Participants allocated to HIIT will perform 14 exercise sessions on a stationary cycle ergometer, over a period of 4-6 weeks before surgery. The sessions, which are individualised, aim to start with ten repeated 1-min blocks of intense exercise with a target of reaching a heart rate exceeding 90% of the age predicted maximum, followed by 1 min of lower intensity cycling. As endurance improves, the duration of exercise is increased to achieve five 2-min intervals of high intensity exercise followed by 2 min of lower intensity cycling. Each training session lasts approximately 30 min. The primary endpoint, change in peak oxygen consumption (Peak VO2) measured during cardiopulmonary exercise testing, is assessed at baseline and before surgery. Secondary endpoints include postoperative complications, length of hospital stay and three clinically validated scores: the surgical recovery scale; the postoperative morbidity survey; and the SF-36 quality of life score. The standard deviation for changes in Peak VO2 will be assessed after the first 30 patients and will be used to calculate the required sample size. DISCUSSION: We want to assess if 14 sessions of HIIT is sufficient to improve Peak VO2 by 2 mL/kg/min in patients undergoing major abdominal surgery and to explore the best clinical endpoint for a subsequent RCT designed to assess if improving Peak VO2 will translate into improving clinical outcomes after surgery. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617000587303 . Registered on 26 April 2017.

Inhibition of calcium/calmodulin-dependent kinase II restores contraction and relaxation in isolated cardiac muscle from type 2 diabetic rats.

BACKGROUND: Calcium/calmodulin-dependent kinase II-delta (CaMKIIδ) activity is enhanced during hyperglycemia and has been shown to alter intracellular calcium handling in cardiomyocytes, ultimately leading to reduced cardiac performance. However, the effects of CaMKIIδ on cardiac contractility during type 2 diabetes are undefined. METHODS: We examined the expression and activation of CaMKIIδ in right atrial appendages from non-diabetic and type 2 diabetic patients (n = 7 patients per group) with preserved ejection fraction, and also in right ventricular tissue from Zucker Diabetic Fatty rats (ZDF) (n = 5-10 animals per group) during early diabetic cardiac dysfunction, using immunoblot. We also measured whole heart function of ZDF and control rats using echocardiography. Then we measured contraction and relaxation parameters of isolated trabeculae from ZDF to control rats in the presence and absence of CaMKII inhibitors. RESULTS: CaMKIIδ phosphorylation (at Thr287) was increased in both the diabetic human and animal tissue, indicating increased CaMKIIδ activation in the type 2 diabetic heart. Basal cardiac contractility and relaxation were impaired in the cardiac muscles from the diabetic rats, and CaMKII inhibition with KN93 partially restored contractility and relaxation. Autocamtide-2-related-inhibitor peptide (AIP), another CaMKII inhibitor that acts via a different mechanism than KN93, fully restored cardiac contractility and relaxation. CONCLUSIONS: Our results indicate that CaMKIIδ plays a key role in modulating performance of the diabetic heart, and moreover, suggest a potential therapeutic role for CaMKII inhibitors in improving myocardial function during type 2 diabetes.

Impaired ventricular filling limits cardiac reserve during submaximal exercise in people with type 2 diabetes.

BACKGROUND: Attenuated increases in ventricular stroke volume during exercise are common in type 2 diabetes and contribute to reduced aerobic capacity. The purpose of this study was to determine whether impaired ventricular filling or reduced systolic ejection were responsible for the attenuated stroke volume reserve in people with uncomplicated type 2 diabetes. METHODS: Peak aerobic capacity and total blood volume were measured in 17 people with diabetes and 16 non-diabetic controls with no evidence of cardiovascular disease. Left ventricular volumes and other systolic and diastolic functional parameters were measured with echocardiography at rest and during semi-recumbent cycle ergometry at 40 and 60% of maximal aerobic power and compared between groups. RESULTS: People with diabetes had reduced peak aerobic capacity and heart rate reserve, and worked at lower workloads than non-diabetic controls. Cardiac output, stroke volume and ejection fraction were not different at rest, but increased less in people with diabetes during exercise. Left ventricular end systolic volume was not different between groups in any condition but end diastolic volume, although not different at rest, was smaller in people with diabetes during exercise. Total blood volume was not different between the groups, and was only moderately associated with left ventricular volumes. CONCLUSIONS: People with type 2 diabetes exhibit an attenuated increase in stroke volume during exercise attributed to an inability to maintain/increase left ventricular filling volumes at higher heart rates. This study is the first to determine the role of filling in the blunted cardiac reserve in adults with type 2 diabetes.

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections.

Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.

Resting heart rate variability and exercise capacity in Type 1 diabetes.

People with type 1 diabetes (T1D) have lower exercise capacity (V̇O2max) than their age-matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty-three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo-plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced-breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying-to-stand, and Valsalva maneuver. Baseline and paced-breathing ECG were analyzed for HRV (frequency-domain). Exercise capacity was determined during an incremental cycle ergometer test while V̇O2, 12-lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, V̇O2max tended to be lower (P = 0.07) and HR reserve was lower (P < 0.01). Resting Total Power (TP) had stronger positive associations with V̇O2max (R2 ≥ 0.3) than all other traditional indicators such as age, resting HR, and self-reported exercise (R2 = 0.042-0.3) in both T1D and CON Alterations in cardiac autonomic modulation are an early manifestation of uncomplicated T1D. Total Power was associated with reduced exercise capacity regardless of group, and these associations were generally stronger than traditional indicators.

ß-Adrenergic Responsiveness in the Type 2 Diabetic Heart: Effects on Cardiac Reserve.

Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly). PURPOSE: This study aimed to determine the chronotopic and inotropic response of the type 2 diabetic heart to ß-adrenergic stimulation. METHODS: Eight people with uncomplicated T2D and seven matched controls performed a dual-energy x-ray absorptiometry scan and V˙O2peak test. Plasma catecholamines were determined at rest and during peak exercise. On a second visit, HR and left ventricular contractility were assessed using echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental ß-adrenergic stimulation (dobutamine). RESULTS: V˙O2peak and HR reserve were lower in T2D (P < 0.05) as expected. Both groups increased norepinephrine comparably (P = 0.23) during peak exercise; however, epinephrine increased less in the T2D group (P < 0.05). The dobutamine dose required to achieve 85% of age-predicted maximal HR was 36% higher in CON (P < 0.05). Resting HR was higher (P < 0.01) and stroke volume indexed to fat free mass was smaller (P < 0.05) in T2D. During dobutamine infusion the response (% change) in HR, end-diastolic volumeFFM, stroke volume, ejection fraction, and cardiac output were not different between the groups. However, HR was higher (P < 0.01) and end-diastolic volume indexed to fat free mass (P < 0.01), stroke volumeFFM (P < 0.01), ejection fraction (P < 0.05), and stroke work (P < 0.01) were lower in T2D. CONCLUSIONS: Although the type 2 diabetic heart worked at smaller volumes, the HR and contractile response to ß-adrenergic stimulation were unaffected by diabetes. The reduced cardiac reserve observed in uncomplicated T2D was not explained by impaired myocardial sympathetic responsiveness but may reflect changes in the loading conditions or function of the diabetic left ventricle.

The Type 2 Diabetic Heart: Its Role in Exercise Intolerance and the Challenge to Find Effective Exercise Interventions.

The metabolic and microvascular benefits of regular exercise for people with diabetes are unequivocal. However, cardiovascular disease, which disproportionately affects people with diabetes, is not reduced by regular exercise, and heart disease remains the leading cause of death for people with type 2 diabetes. 'Subclinical' changes in the function of the diabetic left ventricle are common and reduce cardiac reserve and exercise capacity. This review describes the changes in resting and exercising left ventricular function, and the possible causes of these changes, and introduces the possibility that more vigorous exercise may be needed to improve left ventricular function and reduce rates of cardiovascular disease in people with type 2 diabetes.