The autophagy inhibitor NSC185058 suppresses mTORC1-mediated protein anabolism in cultured skeletal muscle.

The mammalian target of rapamycin (mTOR), and specifically the mTOR complex 1 (mTORC1) is the central regulator of anabolism in skeletal muscle. Among the many functions of this kinase complex is the inhibition of the catabolic process of autophagy; however, less work has been done in investigating the role of autophagy in regulating mTORC1 signaling. Using an in vitro model to better understand the pathways involved, we activated mTORC1 by several different means (growth factors, leucine supplementation, or muscle contraction), alone or with the autophagy inhibitor NSC185058. We found that inhibiting autophagy with NSC185058 suppresses mTORC1 activity, preventing any increase in cellular protein anabolism. These decrements were the direct result of action on the mTORC1 kinase, which we demonstrate, for the first time, cannot function when autophagy is inhibited by NSC185058. Our results indicate that, far from being a matter of unidirectional action, the relationship between mTORC1 and the autophagic cascade is more nuanced, with autophagy serving as an mTORC1 input, and mTORC1 inhibition of autophagy as a form of homeostatic feedback to regulate anabolic signaling. Future studies of cellular metabolism will have to consider this fundamental intertwining of protein anabolism and catabolism, and how it ultimately serves to regulate muscle proteostasis.

Influence of Mechanistic Target of Rapamycin (mTOR)-Regulated Anabolic Pathways on Equine Skeletal Muscle Health.

Skeletal muscle is a highly dynamic organ that is essential for locomotion as well as endocrine regulation in all populations of horses. However, despite the importance of adequate muscle development and maintenance, the mechanisms underlying protein anabolism in horses on different diets, exercise programs, and at different life stages remain obscure. Mechanistic target of rapamycin (mTOR) is a key component of the protein synthesis pathway and is regulated by biological factors such as insulin and amino acid availability. Providing a diet ample in vital amino acids, such as leucine and glutamine, is essential in activating sensory pathways that recruit mTOR to the lysosome and assist in the translation of important downstream targets. When the diet is well balanced, mitochondrial biogenesis and protein synthesis are activated in response to increased exercise bouts in the performing athlete. It is important to note that the mTOR kinase pathways are multifaceted and very complex, with several binding partners and targets that lead to specific functions in protein turnover of the cell, and ultimately, the capacity to maintain or grow muscle mass. Further, these pathways are likely altered across the lifespan, with an emphasis of growth in young horses while decreases in musculature with aged horses appears to be attributable to degradation or other regulators of protein synthesis rather than alterations in the mTOR pathway. Previous work has begun to pinpoint ways in which the mTOR pathway is influenced by diet, exercise, and age; however, future research is warranted to quantify the functional outcomes related to changes in mTOR. Promisingly, this could provide direction on appropriate management techniques to support skeletal muscle growth and maximize athletic potential in differing equine populations.

Understanding the ongoing learning needs of Australian metropolitan, rural and remote paediatricians: Evaluation of a neurology outreach programme.

AIM: The purpose of this study was to evaluate whether a neurology outreach teaching programme delivered via video-teleconferencing (6 × 60 min live sessions every 6-8 weeks) is acceptable, contributes to understanding and meets the neurology learning needs of Australian paediatricians from metropolitan, rural and remote areas. METHODS: A sample of six NSW sites that joined the neurology outreach programme between 2017 and 2019 (Arm 1) and six interstate sites from QLD, WA and TAS who commenced the programme in 2020 (Arm 2) participated. A mixed-methods survey explored participants' learning needs and value of the programme. RESULTS: Forty-six participants submitted programme evaluation surveys (26 arm 1, 20 arm 2); 9 were removed due to insufficient data (n = 37). Quantitative and qualitative data showed the programme was acceptable in format, relevant to practice, appropriate for clinician learning needs, and engaging. Clinicians reported improvement in understanding and confidence. Participants felt more connected/less isolated and up-to-date. Participants reported a positive impact from the programme on approach to neurological problems and ensuing consults, and more differentiated and appropriate paediatric neurology referrals. CONCLUSION: This study validates the live video-teleconference outreach model as an acceptable, effective and important means of providing continuing neurology education for Australian paediatricians.

Myokines derived from contracting skeletal muscle suppress anabolism in MCF7 breast cancer cells by inhibiting mTOR.

There is strong evidence that physical activity has a profound protective effect against multiple types of cancer. Here, we show that this effect may be mediated by factors released from skeletal muscle during simulated exercise, in situ, which suppress canonical anabolic signaling in breast cancer. We report attenuated growth of MCF7 breast cancer cells in the presence of a rodent-derived exercise conditioned perfusate, independent of prior exercise training. This reduction was concomitant with increased levels of DEPTOR protein and reduced mTOR activity.

Cortical and affective regulation of autonomic coordination.

Although anatomical research clearly demonstrates the ability of the sympathetic and parasympathetic branches of the autonomic nervous system to independently influence cardiac function, little research has examined whether coordinated activation is typical or whether the extent of autonomic coordination is situationally dependent. This study examines the extent of coordination between sympathetic (cardiac pre-ejection period: PEP) and parasympathetic (respiratory sinus arrhythmia: RSA) influences on the cardiac function to determine whether coordination is a trait-like between-person characteristic or a state-varying within-person phenomenon, and if so, whether variability in autonomic coordination is modulated by cognitive (P3b amplitude) or affective state. Kindergarten-aged children (n = 257) completed a go/no-go task administered in blocks designed to induce affective states through the delivery of reward (Blocks 1 and 3) and frustration (Block 2). Results from multilevel models that allowed for the simultaneous examination of between-person and within-person associations in the repeated measures data suggested that (a) children with higher overall RSA also tended to have higher overall PEP; (b) at within-person level, RSA and PEP tended to be reciprocally coordinated; but that (c) when frustration invokes cognitive disengagement, coordination between parasympathetic and sympathetic systems demonstrate compensatory coordination. These findings highlight the extent to which the coordination of autonomic systems is a dynamic state-like phenomenon rather than a trait-like individual differences characteristic.

Regulation of cellular anabolism by mTOR: or how I learned to stop worrying and love translation.

The process and regulation of cellular metabolism are extremely complex and accomplished through multiple signalling pathways that operate in parallel, and often experience significant overlap in upstream and downstream a signal transduction. Despite this complexity, single pathway or even single protein activations are commonly used to extrapolate broad characterizations of cellular metabolism. Furthermore, multiple routes for peptide-chain translation initiation exist, some of which may be either exclusive or overlapping depending on the state and environment of the cell. While it may be highly impractical to account for every aspect of metabolic regulation and permutation of mRNA translation, it is important to acknowledge that investigations relating to these pathways are often incomplete and not necessarily indicative of the overall metabolic status. This becomes urgent when considering the role that cellular anabolism plays in both healthy cellular functions and the aetiology of several disease's altered metabolisms. This review describes recent advances in the understanding of cellular metabolic regulation, with specific focus given to the complexity of 'downstream' mRNA translation initiation through both mTOR-dependent and mTOR-independent signallings.

The association between perinatal hypoxia exposure and externalizing symptoms and children's decision making in conditions of uncertainty is moderated by DRD2 genotype.

Variants of the DRD2 Taq1A polymorphism, which have been shown to result in functional differences in dopamine D2 receptors (D2R), have been linked to various externalizing outcomes in adults. However, the neurobiological processes that contribute to these associations are not well understood. The current study investigates gene × environment effects on teacher-rated externalizing behaviors and probabilistic decision making in a sample of 333 children (age 9) enrolled in an ongoing longitudinal study. Findings indicate that externalizing behaviors increased as a function of hypoxic exposure only among individuals carrying the A1 (A1+) allele. Results also indicate that willingness to pursue reward under conditions of maximum uncertainty (50% probability) decreased as a function of hypoxic exposure only among A1- individuals. Among A1 carriers, no association between probability decision making and hypoxic exposure emerged. These findings suggest that hypoxia could influence neural development through different biological pathways depending on D2 receptor genotype, and provide insight into the development of individual differences in behavior and decision making.

Deer response to exclusion from stored cattle feed in Michigan, USA.

Disease and damage from white-tailed deer (Odocoileus virginianus) continually threaten the livelihood of agricultural producers and the economy in the United States, as well as challenge state and federal wildlife managers. Threats can be partially addressed by excluding free-ranging deer from livestock-related resources. Throughout the year, use of stored livestock feed by deer in northern Lower Michigan (MI), USA fluctuates, though their presence is relatively consistent. Since 2008, use of livestock areas and resources by deer has been reduced through intensive efforts by livestock producers in cooperation with state and federal agencies. These efforts focused on excluding deer from stored cattle feed in areas where deer were abundant. We monitored deer activity from Jan 2012 to June 2013 on 6 cattle farms in northern MI using GPS collars to evaluate behavioral effects of excluding deer from stored feed. We characterized areas deer occupied before and after installing 2361 m of fences and gates to exclude deer from stored cattle feed. Following fence installation, 9 deer previously accessing stored feed shifted to patterns of habitat use similar to 5 deer that did not use stored feed. However, continued attempts to regain access to stored feed were made at low frequencies, emphasizing the need to maintain the integrity of fences and keep gates closed for damage prevention and biosecurity.

Human males appear more prepared than females to resolve conflicts with same-sex peers.

The aim of the study was to investigate sex differences in proximate mechanisms that precede the termination of conflicts. In Study 1, we asked women and men to report their intensity of anger in response to hypothetical, common transgressions involving a same-sex roommate. Direct verbal and physical aggression elicited the highest-intensity anger for both sexes, although overall women reported more intense anger than men to all transgressions. In Study 2, we examined sex differences in subjective and physiological reactions to a conflict using a role-playing scenario. Following recall of a conflict involving direct aggression and role-playing a reaction to it, compared with men, women reported their anger would dissipate less quickly and they would take longer to reconcile. Women also exhibited increased heart rate, but little change in cortisol, whereas men exhibited little change in heart rate but increased cortisol production. We interpret the results as indicating that women are less prepared than men to resolve a conflict with a same-sex peer.