The miR-133a, TPM4 and TAp63γ Role in Myocyte Differentiation Microfilament Remodelling and Colon Cancer Progression.

MicroRNAs (miRNAs) play an essential role in the regulation of a number of physiological functions. miR-133a and other muscular miRs (myomiRs) play a key role in muscle cell growth and in some type of cancers. Here, we show that miR133a is upregulated in individuals that undertake physical exercise. We used a skeletal muscle differentiation model to dissect miR-133a's role and to identify new targets, identifying Tropomyosin-4 (TPM4). This protein is expressed during muscle differentiation, but importantly it is an essential component of microfilament cytoskeleton and stress fibres formation. The microfilament scaffold remodelling is an essential step in cell transformation and tumour progression. Using the muscle system, we obtained valuable information about the microfilament proteins, and the knowledge on these molecular players can be transferred to the cytoskeleton rearrangement observed in cancer cells. Further investigations showed a role of TPM4 in cancer physiology, specifically, we found that miR-133a downregulation leads to TPM4 upregulation in colon carcinoma (CRC), and this correlates with a lower patient survival. At molecular level, we demonstrated in myocyte differentiation that TPM4 is positively regulated by the TA isoform of the p63 transcription factor. In muscles, miR-133a generates a myogenic stimulus, reducing the differentiation by downregulating TPM4. In this system, miR-133a counteracts the differentiative TAp63 activity. Interestingly, in CRC cell lines and in patient biopsies, miR-133a is able to regulate TPM4 activity, while TAp63 is not active. The downregulation of the miR leads to TPM4 overexpression, this modifies the architecture of the cell cytoskeleton contributing to increase the invasiveness of the tumour and associating with a poor prognosis. These results add data to the interesting question about the link between physical activity, muscle physiology and protection against colorectal cancer. The two phenomena have in common the cytoskeleton remodelling, due to the TPM4 activity, that is involved in stress fibres formation.

Whole-body Electromyostimulation plus Caloric Restriction in Metabolic Syndrome.

We investigated early effects of Whole-Body Electromyostimulation added to hypocaloric diet on metabolic syndrome features in sedentary middle-aged individuals. We randomly assigned 25 patients to Whole-Body Electromyostimulation plus caloric restriction or caloric restriction alone for 26 weeks. Anthropometrics, blood pressure, fasting glucose and insulin, HOMA-IR, glycated hemoglobin, lipids, uric acid, creatinphosphokynase, C-reactive protein were assessed. Body composition was evaluated with direct-segmental, multi-frequency Bioelectrical Impedance Analysis. Both groups lost approximately 10% of weight, with similar effects on waist circumference and fat mass. Change in free-fat mass was significantly different between groups (caloric restriction -1.5±0.2 vs. Whole-Body Electromyostimulation plus caloric restriction +1.1±0.4 kg, p=0.03). Whole-Body Electromyostimulation plus caloric restriction group experienced greater percent reductions in insulin (-45.5±4.4 vs. -28.2±3.6%, p=0.002), HOMA-IR (-51.3±3.2 vs. -25.1±1.8%, p=0.001), triglycerides (-22.5±2.9 vs. -4.1±1.6%, p=0.004) and triglycerides/HDL (p=0.028). Subjects trained with Whole-Body Electromyostimulation had also significant improvement in systolic pressure (138±4 vs. 126±7 mmHg, p=0.038). No discontinuations for adverse events occurred. In middle-aged sedentary subjects with the metabolic syndrome, Whole-Body Electromyostimulation with caloric restriction for 26 weeks can improve insulin-resistance and lipid profile compared to diet alone. Further studies are needed to ascertain long-term efficacy and feasibility of this approach in individuals with the metabolic syndrome.

Effects of Two Modalities of Whole-body Electrostimulation Programs and Resistance Circuit Training on Strength and Power.

The main purpose of this study was to compare the effects on strength and muscle power of a training program based on two different modalities of whole-body electrostimulation (WB-EMS) with respect to a resistance-training program aimed at improving dynamic strength. Twenty-two subjects participated in this study: Thirteen male (age 25.2±2.8 years; height 1.78±0.1 m; body mass 72.8±6.4 kg; body fat 11.6±2.3%) and nine female (age 28.2±3.5 years; height 1.63±0.05 m; body mass 56.8±7.6 kg; body fat 19.1±4.7%). Participants were randomly assigned to three groups that underwent three different 6-week training programs: two modalities of WB-EMS, based on different electrical parameters (experimental), and circuit training with overloads (control). Force-velocity curves were calculated for each participant before and after treatment. All groups improved their level of strength and muscle power (paired sample t-Test, p<0.01; d>1) with a similar magnitude. No significant differences were observed between groups (two-way 2×3 Anova, p>0.05) at the end of the experimentation. This study suggests that WB-EMS might be considered as a valid and faster alternative - or an important complementary procedure - to a traditional overload-based resistance-training program for the development of the DS.

The circulating miRNAs as diagnostic and prognostic markers.

A large portion of the human genome transcribes RNA sequences that do not code for any proteins. The first of these sequences was identified in 1993, and the best known noncoding RNAs are microRNA (miRNAs). It is now fully established that miRNAs regulate approximately 30% of the known genes that codify proteins. miRNAs are involved in several biological processes, like cell proliferation, differentiation, apoptosis and metastatization. These RNA products regulate gene expression at the post-transcriptional level, modulating or inhibiting protein expression by interacting with specific sequences of mRNAs. Mature miRNAs can be detected in blood plasma, serum and also in a wide variety of biological fluids. They can be found associated with proteins, lipids as well as enclosed in exosome vesicles. We know that circulating miRNAs (C-miRNAs) can regulate several key cellular processes in tissues different from the production site. C-miRNAs behave as endogenous mediators of RNA translation, and an extraordinary knowledge on their function has been obtained in the last years. They can be secreted in different tissue cells and associated with specific pathological conditions. Significant evidence indicates that the initiation and progression of several pathologies are "highlighted" by the presence of specific C-miRNAs, underlining their potential diagnostic relevance as clinical biomarkers. Here we review the current literature on the possible use of this new class of molecules as clinical biomarkers of diseases.