Emerging Strategies Targeting Catabolic Muscle Stress Relief

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitors, myostatin antibodies, β2 adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting

Unfolding cross-linkers as rheology regulators in F-actin networks

We report on the nonlinear mechanical properties of a statistically homogeneous, isotropic semiflexible network cross-linked by polymers containing numerous small unfolding domains, such as the ubiquitous F-actin cross-linker Filamin. We show that the inclusion of such proteins has a dramatic effect on the large strain behavior of the network. Beyond a strain threshold, which depends on network density, the unfolding of protein domains leads to bulk shear softening. Past this critical strain, the network spontaneously organizes itself so that an appreciable fraction of the Filamin cross-linkers are at the threshold of domain unfolding. We discuss via a simple mean-field model the cause of this network organization and suggest that it may be the source of power-law relaxation observed in in vitro and in intracellular microrheology experiments. We present data which fully justifies our model for a simplified network architecture.Comment: 11 pages, 4 figures. to appear in Physical Review

Titin-Actin Interaction: PEVK-Actin-Based Viscosity in a Large Animal

Titin exhibits an interaction between its PEVK segment and the actin filament resulting in viscosity, a speed dependent resistive force, which significantly influences diastolic filling in mice. While diastolic disease is clinically pervasive, humans express a more compliant titin (N2BA:N2B ratio ~0.5–1.0) than mice (N2BA:N2B ratio ~0.2). To examine PEVK-actin based viscosity in compliant titin-tissues, we used pig cardiac tissue that expresses titin isoforms similar to that in humans. Stretch-hold experiments were performed at speeds from 0.1 to 10 lengths/s from slack sarcomere lengths (SL) to SL of 2.15 μm. Viscosity was calculated from the slope of stress-relaxation vs stretch speed. Recombinant PEVK was added to compete off native interactions and this found to reduce the slope by 35%, suggesting that PEVK-actin interactions are a strong contributor of viscosity. Frequency sweeps were performed at frequencies of 0.1–400 Hz and recombinant protein reduced viscous moduli by 40% at 2.15 μm and by 50% at 2.25 μm, suggesting a SL-dependent nature of viscosity that might prevent SL “overshoot” at long diastolic SLs. This study is the first to show that viscosity is present at physiologic speeds in the pig and supports the physiologic relevance of PEVK-actin interactions in humans in both health and disease

Expiratory Muscle Strength Training for Therapy of Pharyngeal Dysphagia in Parkinson's Disease

Background Pharyngeal dysphagia in Parkinson's disease (PD) is a common and clinically relevant symptom associated with poor nutrition intake, reduced quality of life, and aspiration pneumonia. Despite this, effective behavioral treatment approaches are rare. Objective The objective of this study was to verify if 4 week of expiratory muscle strength training can improve pharyngeal dysphagia in the short and long term and is able to induce neuroplastic changes in cortical swallowing processing. Methods In this double-blind, randomized, controlled trial, 50 patients with hypokinetic pharyngeal dysphagia, as confirmed by flexible endoscopic evaluation of swallowing, performed a 4-week expiratory muscle strength training. Twenty-five participants used a calibrated (“active”) device, 25 used a sham handheld device. Swallowing function was evaluated directly before and after the training period, as well as after a period of 3 month using flexible endoscopic evaluation of swallowing. Swallowing-related cortical activation was measured in 22 participants (active:sham; 11:11) using whole-head magnetencephalography. Results The active group showed significant improvement in the flexible endoscopic evaluation of swallowing–based dysphagia score after 4 weeks and after 3 months, whereas in the sham group no significant changes from baseline were observed. Especially, clear reduction in pharyngeal residues was found. Regarding the cortical swallowing network before and after training, no statistically significant differences were found by magnetencephalography examination. Conclusions Four-week expiratory muscle strength training significantly reduces overall dysphagia severity in PD patients, with a sustained effect after 3 months compared with sham training. This was mainly achieved by improving swallowing efficiency. The treatment effect is probably caused by peripheral mechanisms, as no changes in the cortical swallowing network were identified. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Blood pressure and cholesterol level checks as dynamic interrelated screening examinations

This study analysed the determinants of screening uptake for blood pressure and cholesterol level checks. Furthermore, it investigated the presence of possible spillover effects from one type of cardiovascular screening to another type of cardiovascular screening. A dynamic random effects bivariate panel probit model with initial conditions (Wooldridge-type estimator) was adopted for the estimation. The outcome variables were the participation in blood pressure and cholesterol level checks by individuals in a given year. The balanced panel sample of 21,138 observations was constructed from 1,626 individuals from the British Household Panel Survey (BHPS) between 1996 and 2008. The analysis showed the significance of past screening behaviour for both cardiovascular screening examinations. For both cardiovascular screening examinations state dependence exist. The study also shows a significant spillover effect of the cholesterol level check on the blood pressure check and vice versa. Also a poorer health status led to a higher uptake for both types of screening examinations. Changes in recommendations have to consider the fact that taking part in one type of cardiovascular screening examination can influence the decision to take part in the other type of cardiovascular screening examination

Induction of Ankrd1 in dilated cardiomyopathy correlates with the heart failure progression

Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands (ANKRD1, ANKRD2, TRIM63, TRIM55, NBR1, MLP, FHL2, and TCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevated ANKRD1 expression levels marked transition from NYHA < IV to NYHA IV. ANKRD1 expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardial ANKRD1 and serum adiponectin correlated with low BAX/BCL-2 ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM. ANKRD1 expression correlated with reduced cardiac contractility and compliance. The association of ANKRD1 with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure

Исследование кинетики процесса полимеризации 5-норборнен-2,3дикарбоксимид-n-метил ацетата

Previous family studies revealed a large number of calpain 3 (CAPN3) mutations that cause recessive forms of limb girdle muscular dystrophy (LGMD2A) with selective atrophy of the proximal limb muscles. Correlations between the nature and site of a particular mutation and its corresponding phenotype, however, can only be established from homozygous mutations, which are particularly rare in the alternatively spliced NS, IS1 and IS2 regions of CAPN3. Here we identified a sibling pair with LGMD2A-type muscular dystrophy caused by a homozygous Ser606Leu (S606L) substitution in the IS2 linker domain. Normal protein levels, unaltered myofibrillar targeting and conserved calcium-induced autocatalytic activity of the mutated protein could be demonstrated in muscle biopsies from one patient. Despite this inconspicuous modification of the IS2 linker between domains III and IV, both patients developed signs and symptoms of the disease within their second decade of life. The unexpected severity of the clinical manifestation points to the high relevance of the calpain 3-specific IS2 segment between domains III and IV. We conclude that the structural motif around the Ser606 residue represents an important functional site that may regulate the transient activation and limited proteolysis of calpain 3