Skeletal muscle satellite cells, mitochondria, and microRNAs: their involvement in the pathogenesis of ALS

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal motor neuron disorder. It results in progressive degeneration and death of upper and lower motor neurons, protein aggregation, severe muscle atrophy and respiratory insufficiency. Median survival with ALS is between 2 and 5 years from the onset of symptoms. ALS manifests as either familial ALS (FALS) (~10% of cases) or sporadic ALS (SALS), (~90% of cases). Mutations in the copper/zinc (CuZn) superoxide dismutase (SOD1) gene account for ~20% of FALS cases and the mutant SOD1 mouse model has been used extensively to help understand the ALS pathology. As the precise mechanisms causing ALS are not well understood there is presently no cure. Recent evidence suggests that motor neuron degradation may involve a cell non-autonomous phenomenon involving numerous cell types within various tissues. Skeletal muscle is now considered as an important tissue involved in the pathogenesis of ALS by activating a retrograde signaling cascade that degrades motor neurons. Skeletal muscle heath and function are regulated by numerous factors including satellite cells, mitochondria and microRNAs. Studies demonstrate that in ALS these factors show various levels of dysregulation within the skeletal muscle. This review provides an overview of their dysregulation in various ALS models as well as how they may contribute individually and/or synergistically to the ALS pathogenesis

Effect of ageing and exercise training on myokine expression responses to acute exercise

Age-related muscle loss is a major contributor to falls, fraility and mortality. It has been widely suggested that chronic, age-related inflammation contributes to the gradual loss of skeletal muscle mass that occurs with ageing. Indeed, ageing is associated with elevations in a number of circulating inflammatory proteins, many of which have detrimental effects on skeletal muscle growth and protein balance. Exercise training has been shown to reduce chronic inflammation and, therefore, may represent an appropriate means to reduce age-related inflammation and counteract sarcopenia. Yet few studies have evaluated the effect of aging on skeletal muscle expression of inflammatory proteins and the effect of acute and repeated exercise on these factors. The aim of the current study was to determine the effect of 12 weeks of resistance exercise training on the levels of myokines within skeletal muscle, both at rest and following an acute bout of exercise and to examine how these responses may vary in young and older subjects, thus evaluating the potential for exercise to reduce age-related muscle inflammation. Six healthy young (aged 18-25 years) and 8 healthy older men (aged 60-75 years) completed 12 weeks of resistance exercise training. Muscle biopsies were collected before and 2 h after an acute exercise bout at the beginning and the end of the 12 week training period. Muscle tissue was analyzed for the expression of key inflammatory (MCP-1, IL-8, IL-6 and TNF-α) and anti-inflammatory cytokines (IL-10, IL-13 and IL-4) via bead-based multiplex analysis. Acute exercise increased the expression of inflammatory myokines, while anti-inflammatory myokines remained unchanged. In contrast to the hypothesis for this study, neither age nor training had a significant effect on the expression of myokines within skeletal muscle either in the resting state or 2 hours following exercise. However, older individuals displayed an increased inflammatory response to exercise prior to training when compared to younger individuals. Twelve weeks of resistance exercise training appeared to normalize this difference. Given the variability in myokine levels between individuals and the small subject number in the current study, further research is required to confirm this findin

G-CSF does not influence C2C12 myogenesis despite receptor expression in healthy and dystrophic skeletal muscle

Granulocyte-colony stimulating factor (G-CSF) increases recovery of rodent skeletal muscles after injury, and increases muscle function in rodent models of neuromuscular disease. However, the mechanisms by which G-CSF mediates these effects are poorly understood. G-CSF acts by binding to the membrane spanning G-CSFR and activating multiple intracellular signaling pathways. Expression of the G-CSFR within the haematopoietic system is well known, but more recently it has been demonstrated to be expressed in other tissues. However, comprehensive characterization of G-CSFR expression in healthy and diseased skeletal muscle, imperative before implementing G-CSF as a therapeutic agent for skeletal muscle conditions, has been lacking. Here we show that the G-CSFR is expressed in proliferating C2C12 myoblasts, differentiated C2C12 myotubes, human primary skeletal muscle cell cultures and in mouse and human skeletal muscle. In mdx mice, a model of human Duchenne muscular dystrophy (DMD), G-CSF mRNA and protein was down-regulated in limb and diaphragm muscle, but circulating G-CSF ligand levels were elevated. G-CSFR mRNA in the muscles of mdx mice was up-regulated however steady-state levels of the protein were down-regulated. We show that G-CSF does not influence C2C12 myoblast proliferation, differentiation or phosphorylation of Akt, STAT3, and Erk1/2. Media change alone was sufficient to elicit increases in Akt, STAT3, and Erk1/2 phosphorylation in C2C12 muscle cells and suggest previous observations showing a G-CSF increase in phosphoprotein signaling be viewed with caution. These results suggest that the actions of G-CSF may require the interaction with other cytokines and growth factors in vivo, however these data provides preliminary evidence supporting the investigation of G-CSF for the management of muscular dystrophy

Decreased motor cortex excitability mirrors own hand disembodiment during the rubber hand illusion

During the rubber hand illusion (RHI), subjects experience an artificial hand as part of their own body, while the real hand is subject to a sort of\u2019disembodiment\u2019. Can this altered belief about the body also affect physiological mechanisms involved in body-ownership, such as motor control? Here we ask whether the excitability of the motor pathways to the real (disembodied) hand are affected by the illusion. Our results show that the amplitude of the motor-evoked potentials recorded from the real hand is significantly reduced, with respect to baseline, when subjects in the synchronous (but not in the asynchronous) condition experience the fake hand as their own. This finding contributes to the theoretical understanding of the relationship between body-ownership and motor system, and provides the first physiological evidence that a significant drop in motor excitability in M1 hand circuits accompanies the disembodiment of the real hand during the RHI experience

Results of a phase I-II study on laser therapy for vaginal side effects after radiotherapy for cancer of uterine cervix or endometrium

Women who have previously received radiotherapy (RT) for gynecologic cancer often suffer from vaginal fibrosis and stenosis. The success of “non-ablative” laser therapy for postmenopausal vaginal atrophy has led to the idea of testing the laser in patients submitted to RT. In this prospective observational study, we selected patients who underwent pelvic RT followed by vaginal laser treatment. We scheduled three treatment sessions (at T0–T1–T2) and three controls (at T1–T2–T3) one month apart. The follow-up (at T4) was carried out six months after the last treatment. Vaginal Health Index (VHI) and vaginal length were evaluated. Sexual function was assessed through Female Sexual Function Index (FSFI). Overall, 43 patients with severe vaginal shortening, atrophy and stenosis was enrolled and treated with intravaginal non-ablative CO2 laser. We observed a progressive increase in vaginal length of 9% (p = 0.03) at T2 and 28% (p < 0.0001) at T3; effects were maintained at T4 (p < 0.0001). After the first application VHI showed a significant improvement of 57% at T3 (p < 0.0001). The results were maintained at T4 (p < 0.0001). No changes were found in FSFI. All procedures were well tolerated. In conclusion, laser therapy improved vaginal length and VHI in women undergoing pelvic RT; prospective studies are needed

Associations of sedentary time patterns and TV viewing time with inflammatory and endothelial function biomarkers in children

OBJECTIVE: Investigate associations of TV viewing time and accelerometry-derived sedentary time with inflammatory and endothelial function biomarkers in children. METHODS: Cross-sectional analysis of 164 7-10-year-old children. TV viewing time was assessed by parental proxy report and total and patterns of sedentary time accumulation (e.g. prolonged bouts) were assessed by accelerometry. C-reactive protein (CRP), homeostasis model assessment of insulin resistance, interleukin-2, -6, -8, -10, tumour necrosis factor alpha, adiponectin, resistin, brain-derived neurotrophic factor, soluble intercellular and vascular adhesion molecule 1, plasminogen activator inhibitor 1 and soluble E-selectin were assessed. Generalised linear models assessed the associations of TV viewing and sedentary time with biomarkers, adjusting for sex, waist circumference, moderate- to vigorous-intensity physical activity and diet density. RESULTS: Each additional h week(-1) of TV viewing was associated with 4.4% (95% CI: 2.1, 6.7) greater CRP and 0.6% (0.2, 1.0) greater sVCAM-1 in the fully adjusted model. The association between frequency and duration of 5-10 min bouts of sedentary time and CRP was positive after adjustment for sex and waist circumference but attenuated after adjustment for diet density. CONCLUSIONS: This study suggests that TV viewing was unfavourably associated with several markers of inflammation and endothelial dysfunction. The detrimental association between 5 and 10 min bouts of sedentary time and CRP approached significance, suggesting that further research with a stronger study design (longitudinal and/or experimental) is needed to better understand how the accumulation of sedentary time early in life may influence short and longer term health

Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL

The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL)(1,2). Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3. This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL. Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation. Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL. Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL

A simple approach to ranking differentially expressed gene expression time courses through Gaussian process regression.

BACKGROUND: The analysis of gene expression from time series underpins many biological studies. Two basic forms of analysis recur for data of this type: removing inactive (quiet) genes from the study and determining which genes are differentially expressed. Often these analysis stages are applied disregarding the fact that the data is drawn from a time series. In this paper we propose a simple model for accounting for the underlying temporal nature of the data based on a Gaussian process. RESULTS: We review Gaussian process (GP) regression for estimating the continuous trajectories underlying in gene expression time-series. We present a simple approach which can be used to filter quiet genes, or for the case of time series in the form of expression ratios, quantify differential expression. We assess via ROC curves the rankings produced by our regression framework and compare them to a recently proposed hierarchical Bayesian model for the analysis of gene expression time-series (BATS). We compare on both simulated and experimental data showing that the proposed approach considerably outperforms the current state of the art. CONCLUSIONS: Gaussian processes offer an attractive trade-off between efficiency and usability for the analysis of microarray time series. The Gaussian process framework offers a natural way of handling biological replicates and missing values and provides confidence intervals along the estimated curves of gene expression. Therefore, we believe Gaussian processes should be a standard tool in the analysis of gene expression time series

The Italian fund for Alzheimer's and other dementias: strategies and objectives to face the dementia challenge

The Italian Fund for Alzheimer's and other dementias was approved and signed in December 2021. The Fund is financed with 15 million euros in three years. The main goal is to provide new strategies in the field of dementia with a Public Health perspective. The Fund includes eight main activities that will be monitored and supervised by the Italian National Institute of Health: 1) development of a guideline for the assessment, management and support for people with dementia and their families/carers; 2) updating of the Dementia National Plan (DNP); 3) implementation of the documents of the DNP; 4) conducting surveys dedicated to the Italian Dementia Services; 5) promotion of dementia prevention strategies; 6) training strategies for healthcare professionals, families and caregivers; 7) creation of a National Electronic Record for Dementia; 8) evaluation and monitoring of activities promoted by Regions and Autonomous Provinces in the field of dementia, together with the dementia National Permanent Table. These activities are outlined in detail in the present paper

Low-Temperature Polymorphic Phase Transition in a Crystalline Tripeptide L-Ala-L-Pro-Gly·H2O Revealed by Adiabatic Calorimetry

We demonstrate application of precise adiabatic vacuum calorimetry to observation of phase transition in the tripeptide l-alanyl-l-prolyl-glycine monohydrate (APG) from 6 to 320 K and report the standard thermodynamic properties of the tripeptide in the entire range. Thus, the heat capacity of APG was measured by adiabatic vacuum calorimetry in the above temperature range. The tripeptide exhibits a reversible first-order solid-to-solid phase transition characterized by strong thermal hysteresis. We report the standard thermodynamic characteristics of this transition and show that differential scanning calorimetry can reliably characterize the observed phase transition with <5 mg of the sample. Additionally, the standard entropy of formation from the elemental substances and the standard entropy of hypothetical reaction of synthesis from the amino acids at 298.15 K were calculated for the studied tripeptide.National Institute of Biomedical Imaging and Bioengineering (U.S.) (EB-003151)National Institute of Biomedical Imaging and Bioengineering (U.S.) (EB-001960)National Institute of Biomedical Imaging and Bioengineering (U.S.) (EB-002026