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Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.DOI: http://dx.doi.org/10.7554/eLife.09406.001

The purpose of this study was to develop a regression equation to predict maximal oxygen uptake (VO2max) based on nonexercise (N-EX) data. All participants (N = 100), ages 18-65 years, successfully completed a maximal graded exercise test (GXT) to assess VO2max (M = 39.96 mL x kg(-1) x min(-1), SD = 9.54). The N-EX data collected just before the maximal GXT included the participant's age; gender; body mass index (BMI); perceived functional ability (PFA) to walk, jog, or run given distances; and current physical activity (PA-R) level. Multiple linear regression generated the following N-EX prediction equation (R = .93, SEE = 3.45 mL x kg(-1) x min(-1), % SEE = 8.62): VO2max (mL x kg(-1) x min(-1)) = 48.0730 + (6.1779 x gender; women = 0, men = 1) - (0. 2463 x age) - (0.6186 x BMI) + (0.7115 x PFA) + (0.6709 x PA-R). Cross validation using PRESS (predicted residual sum of squares) statistics revealed minimal shrinkage (R(p) = .91 and SEE(p) = 3.63 mL x kg(-1) x min(-1)); thus, this model should yield acceptable accuracy when applied to an independent sample of adults (ages 18-65 years) with a similar cardiorespiratory fitness level. Based on standardized beta-weights, the PFA variable (0.41) was the most effective at predicting VO2max followed by age (-0.34), gender (0.33), BMI (-0.27), and PA-R (0.16). This study provides a N-EX regression model that yields relatively accurate results and is a convenient way to predict VO2max in adult men and women.