The extracellular signals which regulate the myogenic program are transduced to the nucleus by mitogenactivated protein kinases (MAPKs). We have investigated the role of two MAPKs, p38 and extracellular signal-regulated kinase (ERK), whose activities undergo significant changes during muscle differentiation. p38 is rapidly activated in myocytes induced to differentiate. This activation differs from those triggered by stress and cytokines, because it is not linked to Jun-N-terminal kinase stimulation and is maintained during the whole process of myotube formation. Moreover, p38 activation is independent of a parallel promyogenic pathway stimulated by insulin-like growth factor 1. Inhibition of p38 prevents the differentiation program in myogenic cell lines and human primary myocytes. Conversely, deliberate activation of endogenous p38 stimulates muscle differentiation even in the presence of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-responsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of chromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic conversion is reduced in mouse embryonic fibroblasts derived from p38␣ ؊/؊ embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ERK shows a biphasic activation profile, with peaks of activity in undifferentiated myoblasts and postmitotic myotubes. Importantly, activation of ERK is inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic responses (i.e., hypertrophic growth) in myotubes.In the past decade, much has been learned about the molecular mechanisms that govern myogenesis owing mainly to the discovery of two groups of myogenic transcription factors (4,45,62). The first group includes the myogenic regulatory factors (MRFs), which belong to the basic helix-loop-helix (bHLH) protein family. This MRF group consists of four members: Myf5, MyoD, myogenin, and MRF4, all of which are specifically expressed in skeletal muscles. One of the unique features of these MRFs is that when they are ectopically expressed in fibroblasts or certain other nonmuscle cells, each has the ability to initiate the myogenic program and convert nonmuscle cells to myogenic derivatives (9, 59). Myogenic bHLH proteins heterodimerize with other ubiquitous bHLH proteins (like the E2A gene products, E12, and E47) to efficiently bind a consensus DNA site: CANNTG (also called the E box) (4, 33). The second group of transcription factors important in muscle differentiation consists of four different myocyte enhancer binding factor 2 (MEF2) proteins, which belong to the MADS box...

Metastatic cancer cells have the ability to both degrade and migrate through the extracellular matrix (ECM). Invasiveness can be correlated with the presence of dynamic actin-rich membrane structures called podosomes or invadopodia. We showed previously that the adaptor protein tyrosine kinase substrate with five Src homology 3 domains (Tks5)/Fish is required for podosome/invadopodia formation, degradation of ECM, and cancer cell invasion in vivo and in vitro. Here, we describe Tks4, a novel protein that is closely related to Tks5. This protein contains an amino-terminal Phox homology domain, four SH3 domains, and several proline-rich motifs. In Src-transformed fibroblasts, Tks4 is tyrosine phosphorylated and predominantly localized to rosettes of podosomes. We used both short hairpin RNA knockdown and mouse embryo fibroblasts lacking Tks4 to investigate its role in podosome formation. We found that lack of Tks4 resulted in incomplete podosome formation and inhibited ECM degradation. Both phenotypes were rescued by reintroduction of Tks4, whereas only podosome formation, but not ECM degradation, was rescued by overexpression of Tks5. The tyrosine phosphorylation sites of Tks4 were required for efficient rescue. Furthermore, in the absence of Tks4, membrane type-1 matrix metalloproteinase (MT1-MMP) was not recruited to the incomplete podosomes. These findings suggest that Tks4 and Tks5 have overlapping, but not identical, functions, and implicate Tks4 in MT1-MMP recruitment and ECM degradation.

Purpose The aim of the study was to describe the mode, frequency, duration, and intensity of physical activity among pregnant women, to explore whether these women reached the recommended levels of activity, and to explore how these patterns changed during pregnancy. Methods This study, as part of the third phase of the Pregnancy, Infection, and Nutrition Study, investigated physical activity among 1482 pregnant women. A recall of the different modes, frequency, duration, and intensity of physical activity during the past week was assessed in two telephone interviews at 17–22 and 27–30 weeks’ gestation. Results Most women reported some type of physical activity during both time periods. Child and adult care giving, indoor household, and recreational activities constituted the largest proportion of total reported activity. The overall physical activity level decreased during pregnancy, particularly in care giving, outdoor household, and recreational activity. Women who were active during the second and third trimesters reported higher levels of activity in all modes of activity than those who became active or inactive during pregnancy. The majority did not reach the recommended level of physical activity. Conclusion These data suggest that self-reported physical activity decreased from the second to third trimester and only a small proportion reached the recommended level of activity during pregnancy. Further research is needed to explore if physical activity rebounds during the postpartum period.

No abstract

No abstract

Objective We conducted a laboratory-based calibration study to determine relevant cutpoints for a hip-worn accelerometer among women ≥60 years, considering both type and filtering of counts. Methods Two hundred women wore an ActiGraph GT3X+ accelerometer on their hip while performing eight laboratory-based activities. Oxygen uptake was measured using an Oxycon portable calorimeter. Accelerometer data were analyzed in 15-second epochs for both normal and low frequency extension (LFE) filters. Receiver operating characteristic (ROC) curve analyses were used to calculate cutpoints for sedentary, light (low and high), and moderate to vigorous physical activity (MVPA) using the vertical axis and vector magnitude (VM) counts. Results Mean age was 75.5 years (standard deviation 7.7). The Spearman correlation between oxygen uptake and accelerometry ranged from 0.77 to 0.85 for the normal and LFE filters and for both the vertical axis and VM. The area under the ROC curve was generally higher for VM compared to the vertical axis, and higher for cutpoints distinguishing MVPA compared to sedentary and light low activities. The VM better discriminated sedentary from light low activities compared to the vertical axis. The area under the ROC curves were better for the LFE filter compared to the normal filter for the vertical axis counts, but no meaningful differences were found by filter type for VM counts. Conclusion The cutpoints derived for this study among women ≥60 years can be applied to ongoing epidemiologic studies to define a range of physical activity intensities.

The US physical activity (PA) recommendations were based primarily on studies in which self-reported data were used. Studies that include accelerometer-assessed PA and sedentary behavior can contribute to these recommendations. In the present study, we explored the associations of PA and sedentary behavior with all-cause and cardiovascular disease (CVD) mortality in a nationally representative sample. Among the 2003-2006 National Health and Nutrition Examination Survey cohort, 3,809 adults 40 years of age or older wore an accelerometer for 1 week and self-reported their PA levels. Mortality data were verified through 2011, with an average of 6.7 years of follow-up. We used Cox proportional hazards models to obtain adjusted hazard ratios and 95% confidence intervals. After excluding the first 2 years, there were 337 deaths (32% or 107 of which were attributable to CVD). Having higher accelerometer-assessed average counts per minute was associated with lower all-cause mortality risk: When compared with the first quartile, the adjusted hazard ratio was 0.37 (95% confidence interval: 0.23, 0.59) for the fourth quartile, 0.39 (95% confidence interval: 0.27, 0.57) for the third quartile, and 0.60 (95% confidence interval: 0.45, 0.80) second quartile. Results were similar for CVD mortality. Lower all-cause and CVD mortality risks were also generally observed for persons with higher accelerometer-assessed moderate and moderate-to-vigorous PA levels and for self-reported moderate-to-vigorous leisure, household and total activities, as well as for meeting PA recommendations. Accelerometer-assessed sedentary behavior was generally not associated with all-cause or CVD mortality in fully adjusted models. These findings support the national PA recommendations to reduce mortality.

Purpose Parks offer a free option for physical activity in many communities. How much time people spend using parks and the contribution that parks makes to their physical activity is not known. This study describes patterns of park use and physical activity among a diverse adult sample. Methods From five US states, 238 adults enrolled in or near 31 study parks. Participants wore a global positioning system (GPS) monitor (Qstarz BT-Q1000X) and an ActiGraph accelerometer (GT1M) concurrently for three weeks. Parks were mapped from local and national park shape files. Park visits and travel to and from the parks were derived from the objective data. Results Participants visited parks a median of 2.3 times/week and park visits lasted a median of 42.0 minutes. Overall, participants engaged in a median of 21.7 minutes/day of moderate activity and 0.1 minutes/day of vigorous activity, with an average of 8.2% of all moderate and 9.4% of all vigorous activity occurring within the parks. Among those with at least one park visit (n=218), counts per minute, moderate, moderate to vigorous physical activity (MVPA), number and time in MVPA bouts/day, and sedentary behavior were all higher on days when a park was visited compared to days when a park was not visited. Considering several definitions of active travel, walking or bicycling to and from the park added an additional 3.7 to 6.6 mean minutes of MVPA per park visit. Conclusion Parks contributed as a place and destination for physical activity, but were underutilized. One of the next steps in this line of inquiry is to understand characteristics of parks used more often as a place and destination for physical activity.