Skeletal muscle and kidney crosstalk in chronic kidney disease

The functioning of complex organisms requires a constant and delicate balance of processes both between and within cells, tissues, and organ systems. There is growing appreciation for the role of signalling crosstalk connecting different organ systems of the body, even from tissues traditionally classified as “inert” in terms of their capacity to produce chemical signals that can act on other organ systems. Many of these secreted molecules have been shown to contribute to, or exacerbate, a variety of functions and diseases in other organ systems, even if the two organs are not functionally linked. For example, there is a strong association with skeletal muscle atrophy and dysfunction in patients with chronic kidney disease (CKD). Identification of molecules produced and secreted by skeletal muscle has existed for some time, and there is emerging evidence that skeletal muscle may directly affect kidney function. Conversely, factors produced and secreted by the kidneys in various models of CKD have been shown to contribute to reduced muscle functionality. This review will focus on crosstalk in both directions between skeletal muscle and the kidneys. The emphasis will be on direct interaction between these organs using examples of secreted factors that are produced by the muscle or kidneys (including activin A, myostatin, microRNA’s, irisin and mitsugumin 53),often under pathophysiological conditions. Our understanding of how the kidneys and skeletal muscle interact with each other is key to elucidating the pathophysiology processes that drive health and disease

Perspectives of applied collaborative sport science research within professional team sports

The purpose of the study was to examine the perspectives of both academics and practitioners in relation to forming applied collaborative sports science research within team sports. Ninety-three participants who had previously engaged in collaborative research partnerships within team sports completed an online survey which focused on motivations and barriers for forming collaborations using blinded sliding scale (0-100) and rank order list. Research collaborations were mainly formed to improve team performance (Academic: 73.6 ± 23.3; Practitioner: 84.3 ± 16.0; ES = 0.54, small). Academics ranked journal articles importance significantly higher than practitioners (Academic: Mrank = 53.9; Practitioner 36.0; z = -3.18, p = .001, p < q). However, practitioners rated one-to-one communication as more preferential (Academic: Mrank = 41.3; Practitioner 56.1; z = -2.62, p = .009, p < q). Some potential barriers were found in terms of staff buy in (Academic: 70.0 ± 25.5; Practitioner 56.8 ± 27.3; ES = 0.50, small) and funding (Academic: 68.0 ± 24.9; Practitioner: 67.5 ± 28.0; ES = 0.02, Trivial). Both groups revealed low motivation for invasive mechanistic research (Academic: 36.3 ± 24.2; Practitioner: 36.4 ± 27.5; ES = 0.01, trivial), with practitioners have a preference towards ‘fast’ type research. There was a general agreement between academics and practitioners for forming research collaborations. Some potential barriers still exist (e.g. staff buy in and funding), with practitioners preferring ‘fast’ informal research dissemination compared to the ‘slow’ quality control approach of academics

The effects of knee injury on skeletal muscle function, Na+, K+-ATPase content, and isoform abundance.

While training upregulates skeletal muscle Na+, K+‐ATPase (NKA), the effects of knee injury and associated disuse on muscle NKA remain unknown. This was therefore investigated in six healthy young adults with a torn anterior cruciate ligament, (KI; four females, two males; age 25.0 ± 4.9 years; injury duration 15 ± 17 weeks; mean ± SD) and seven age‐ and BMI‐matched asymptomatic controls (CON; five females, two males). Each participant underwent a vastus lateralis muscle biopsy, on both legs in KI and one leg in CON. Muscle was analyzed for muscle fiber type and cross‐sectional area (CSA), NKA content ([3H]ouabain binding), and α1–3 and β1–2 isoform abundance. Participants also completed physical activity and knee function questionnaires (KI only); and underwent quadriceps peak isometric strength, thigh CSA and postural sway assessments in both injured and noninjured legs. NKA content was 20.1% lower in the knee‐injured leg than the noninjured leg and 22.5% lower than CON. NKA α2 abundance was 63.0% lower in the knee‐injured leg than the noninjured leg, with no differences in other NKA isoforms. Isometric strength and thigh CSA were 21.7% and 7.1% lower in the injured leg than the noninjured leg, respectively. In KI, postural sway did not differ between legs, but for two‐legged standing was 43% higher than CON. Hence, muscle NKA content and α2 abundance were reduced in severe knee injury, which may contribute to impaired muscle function. Restoration of muscle NKA may be important in rehabilitation of muscle function after knee and other lower limb injury

Docosahexaenoic acid counteracts palmitate-induced endoplasmic reticulum stress in C2C12 myotubes: Impact on muscle atrophy

Lipid accumulation in skeletal muscle results in dysregulation of protein meta- bolism and muscle atrophy. We previously reported that treating C2C12 myo- tubes with palmitate (PA), a saturated fatty acid, increases the overall rate of proteolysis via activation of the ubiquitin-proteasome and autophagy systems; co-treatment with the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents the PA-induced responses. Others have reported that PA induces endoplasmic reticulum (ER) stress which initiates the unfolded pro- tein response (UPR), a collective group of responses that can lead to activa- tion of caspase-mediated proteolysis and autophagy. Presently, we tested the hypothesis that DHA protects against PA-induced ER stress/UPR and its atro- phy-related responses in muscle cells. C2C12 myotubes were treated with 500 lmol/L PA and/or 100 lmol/L DHA for 24 h. Proteins and mRNA asso- ciated with ER stress/UPR, autophagy, and caspase-3 activation were evalu- ated. PA robustly increased the phosphorylation of protein kinase R (PKR)- like ER kinase (PERK) and eukaryotic initiation factor 2a (eIF2a). It also increased the mRNAs encoding activating transcription factor 4 (ATF4), spliced X-box binding protein 1 (XBP1s), C/EBP homologous protein (CHOP), and autophagy-related 5 (Atg5) as well as the protein levels of the PERK target nuclear factor erythroid 2-related factor (Nrf2), CHOP, and cleaved (i.e., activated) caspase-3. Co-treatment with DHA prevented all of the PA-induced responses. Our results indicate that DHA prevents PA- induced muscle cell atrophy, in part, by preventing ER stress/UPR, a process that leads to activation of caspase-mediated proteolysis and an increase in expression of autophagy-related genes

Salbutamol effects on systemic potassium dynamics during and following intense continuous and intermittent exercise

Purpose: Salbutamol inhalation is permissible by WADA in athletic competition for asthma management and affects potassium regulation, which is vital for muscle function. Salbutamol effects on arterial potassium concentration ([K+]a) during and after high-intensity continuous exercise (HIcont) and intermittent exercise comprising repeated, brief sprints (HIint), and on performance during HIint are unknown and were investigated. Methods: Seven recreationally active men participated in a double-blind, randomised, cross-over design, inhaling 1000 µg salbutamol or placebo. Participants cycled continuously for 5 min at 40 % V ˙ O2peak and 60 % V ˙ O2peak, then HIcont (90 s at 130 % V ˙ O2peak), 20 min recovery, and then HIint (3 sets, 5 × 4 s sprints), with 30 min recovery. Results: Plasma [K+]a increased throughout exercise and subsequently declined below baseline (P < 0.001). Plasma [K+]a was greater during HIcont than HIint (P < 0.001, HIcont 5.94 ± 0.65 vs HIint set 1, 4.71 ± 0.40 mM); the change in [K+]a from baseline (Δ[K+]a) was 2.6-fold greater during HIcont than HIint (P < 0.001). The Δ[K+] throughout the trial was less with salbutamol than placebo (P < 0.001, treatment main effect, 0.03 ± 0.67 vs 0.22 ± 0.69 mM, respectively); and remained less after correction for fluid shifts (P < 0.001). The Δ[K+] during HIcont was less after salbutamol (P < 0.05), but not during HIint. Blood lactate, plasma pH, and the work output during HIint did not differ between trials. Conclusions: Inhaled salbutamol modulated the [K+]a rise across the trial, comprising intense continuous and intermittent exercise and recovery, lowering Δ[K+] during HIcont. The limited [K+]a changes during HIint suggest that salbutamol is unlikely to influence systemic [K+] during periods of intense effort in intermittent sports

Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle

Introduction: It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles. Methods: Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water. Post NAC treatment animals were euthanised and the EDL muscles dissected out and placed in an organ bath where the muscle was attached to a force transducer to measure contractile properties and susceptibility to force loss from eccentric contractions. After the contractile measurements had been made the EDL muscle was blotted and weighed. In order to assess the degree of pathological fiber branching mdx EDL muscles were treated with collagenase to release single fibers. For counting and morphological analysis single EDL mdx skeletal muscle fibers were viewed under high magnification on an inverted microscope. Results: During the six-week treatment phase NAC reduced body weight gain in three- to nine-week-old mdx and littermate control mice without effecting fluid intake. NAC treatment also significantly reduced the mdx EDL muscle mass and abnormal fiber branching and splitting. Discussion: We propose chronic NAC treatment reduces the inflammatory response and degenerative cycles in the mdx dystrophic EDL muscles resulting in a reduction in the number of complexed branched fibers reported to be responsible for the dystrophic EDL muscle hypertrophy

Minocycline treatment reduces mass and force output from fast-twitch mouse muscles and inhibits myosin production in C2C12 myotubes

Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis. Mice were injected with minocycline (40 mg/kg i.p.) daily for 5 days and sacrificed at day six. Fast-twitch EDL, TA muscles and slow-twitch soleus muscles were dissected out, the TA muscle was snap-frozen and the remaining muscles were attached to force transducer whilst maintained in an organ bath. In C2C12 myotubes, minocycline was applied to the media at a final concentration of 10 µg/mL for 48 h. In minocycline treated mice absolute maximal force was lower in fast-twitch EDL while in slow-twitch soleus there was an increase in the time to peak and relaxation of the twitch. There was no effect of minocycline treatment on the other contractile parameters measured in isolated fast- and slow-twitch muscles. In C2C12 cultured cells, minocycline treatment significantly reduced both myosin heavy chain content and protein synthesis without visible changes to myotube morphology. In the TA muscle there was no significant changes in myosin heavy chain content. These results indicate that high dose minocycline treatment can cause a reduction in maximal isometric force production and mass in fast-twitch EDL and impair protein synthesis during myogenesis in C2C12 cultured cells. These findings have important implications for future studies investigating the efficacy of minocycline treatment in neuromuscular or other muscle-atrophy inducing conditions

Parental Efficacy Moderates the Association Between Empathy and Burden Among Parents of Children Admitted to a Psychiatric Ward

Empathy is considered a positive aspect of caregiving, although in certain circumstances, being empathic might increase the burden of caregivers. The current study assessed the associations between empathy, parental efficacy, and family burden among parents of children who were hospitalized in a psychiatric unit. Specifically, we examined whether the association between empathy and family burden was moderated by the parents' sense of self-efficacy. Seventy parents of children with psychiatric disorders, hospitalized in an inpatient psychiatric unit, filled out questionnaires of empathy, parental efficacy, and family burden. Results supported a moderating role of parental efficacy between empathy and family burden (interaction effect: beta = -1.72, p = .0406). Specifically, empathy was positively related to family burden among parents with low self-efficacy (conditional effect = 0.70, p = .032) and negatively related to family burden among parents with high self-efficacy (conditional effect = -0.39, p = N.S). Implications for practice include the importance of self-efficacy and address the possible negative implications of empathy among parents of children treated in a psychiatric hospital

TrustedPals: Secure Multiparty Computation Implemented with Smart Cards

We study the problem of Secure Multi-party Computation (SMC) in a model where individual processes contain a tamper-proof security module, and introduce the TrustedPals framework, an efficient smart card based implementation of SMC for any number of participating entities in such a model. Security modules can be trusted by other processes and can establish secure channels between each other. However, their availability is restricted by their host, that is, a corrupted party can stop the computation of its own security module as well as drop any message sent by or to its security module. We show that in this model SMC can be implemented by reducing it to a fault-tolerance problem at the level of security modules. Since the critical part of the computation can be executed locally on the smart card, we can compute any function securely with a protocol complexity which is polynomial only in the number of processes (that is, the complexity does not depend on the function which is computed), in contrast to previous approaches

Transcriptome and chromatin alterations in social fear indicate association of MEG3 with successful extinction of fear

Social anxiety disorder is characterized by a persistent fear and avoidance of social situations, but available treatment options are rather unspecific. Using an established mouse social fear conditioning (SFC) paradigm, we profiled gene expression and chromatin alterations after the acquisition and extinction of social fear within the septum, a brain region important for social fear and social behaviors. Here, we particularly focused on the successful versus unsuccessful outcome of social fear extinction training, which corresponds to treatment responsive versus resistant patients in the clinics. Validation of coding and non-coding RNAs revealed specific isoforms of the long non-coding RNA (lncRNA) Meg3 regulated, depending on the success of social fear extinction. Moreover, PI3K/AKT was differentially activated with extinction success in SFC-mice. In vivo knockdown of specific Meg3 isoforms increased baseline activity of PI3K/AKT signaling, and mildly delayed social fear extinction. Using ATAC-Seq and CUT&RUN, we found alterations in the chromatin structure of specific genes, which might be direct targets of lncRNA Meg3