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. 2017 Jul;112(4):48.
doi: 10.1007/s00395-017-0639-9. Epub 2017 Jun 24.

Exogenous GDF11 Induces Cardiac and Skeletal Muscle Dysfunction and Wasting

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Free PMC article

Exogenous GDF11 Induces Cardiac and Skeletal Muscle Dysfunction and Wasting

Teresa A Zimmers et al. Basic Res Cardiol. .
Free PMC article

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Abstract

Growth differentiation factor 11 (GDF11), a TGF-beta superfamily member, is highly homologous to myostatin and essential for embryonic patterning and organogenesis. Reports of GDF11 effects on adult tissues are conflicting, with some describing anti-aging and pro-regenerative activities on the heart and skeletal muscle while others opposite or no effects. Herein, we sought to determine the in vivo cardiac and skeletal muscle effects of excess GDF11. Mice were injected with GDF11 secreting cells, an identical model to that used to initially identify the in vivo effects of myostatin. GDF11 exposure in mice induced whole body wasting and profound loss of function in cardiac and skeletal muscle over a 14-day period. Loss of cardiac mass preceded skeletal muscle loss. Cardiac histologic and echocardiographic evaluation demonstrated loss of ventricular muscle wall thickness, decreased cardiomyocyte size, and decreased cardiac function 10 days following initiation of GDF11 exposure. Changes in skeletal muscle after GDF11 exposure were manifest at day 13 and were associated with wasting, decreased fiber size, and reduced strength. Changes in cardiomyocytes and skeletal muscle fibers were associated with activation of SMAD2, the ubiquitin-proteasome pathway and autophagy. Thus, GDF11 over administration in vivo results in cardiac and skeletal muscle loss, dysfunction, and death. Here, serum levels of GDF11 by Western blotting were 1.5-fold increased over controls. Although GDF11 effects in vivo are likely dose, route, and duration dependent, its physiologic changes are similar to myostatin and other Activin receptors ligands. These data support that GDF11, like its other closely related TGF-beta family members, induces loss of cardiac and skeletal muscle mass and function.

Keywords: Aging; Atrophy; Autophagy; Cachexia; Cardiac function; Cardiac hypertrophy; GDF-11; GDF11; Growth/differentiation factor-11; Myostatin; SMAD2; Wasting.

Figures

Figure 1
Figure 1. Heart and Cardiomyocyte Size Decrease with GDF11 Overexpression
(A and B) Heart weights (HW) of normal, control, and GDF11 mice at sacrifice, normalized to (A) initial body weight (IBW), (B) tibia length (TL), and (C) to final body weight (FBW). Heart weights of normal mice (n=4) taken at day 13 are shown to the left of the dashed vertical line, and those of control and GDF11 mice at day 10 (n=5 and n=8, respectively) and at day 13 (n=5 and n=7, respectively) are compared to the right of the line. Horizontal lines with error bars indicate mean ± SEM. (D) Gross anatomy (top row of figure on left, 5 mm scale bar) and hematoxylin and eosin staining (cross-section, middle row, 3 mm scale bar; 40x magnification, bottom row) of normal, control, and GDF11 mouse hearts at day 13. LV, left ventricle; RV, right ventricle. (E) Mean cardiomyocyte fiber cross-sectional area (CSA) of normal, control, and GDF11 mice at day 13. Data are mean ± SD. (F) Histogram of cardiomyocyte CSA for normal, control, and GDF11 mice at day 13. Numerical data of mean cardiomyocyte CSA (data are mean ± SEM) and number of fibers measured are shown in table below. (G) Gene expression analyses of cardiac muscle in normal (left of dashed vertical line, measured at day 13), control, and GDF11 mice at days 10 and 13. Data are represented as mean fold change ± SD. Fold change for atrogin-1 and MuRF1 were calculated using reference gene TBP, while data for all other genes were calculated using reference gene 18S. (H) Western blotting analyses to determine SMAD2 levels in normal, control, and GDF11 mice at day 13. Horizontal lines with error bars indicate mean ± SD. Statistically significant differences are indicated at p < 0.05 (*), p < 0.01 (**), p < 0.001 (***) and p < 0.0001 (****).
Figure 2
Figure 2. Echocardiographic Measurements in Mice with GDF11 Overexpression Demonstrate Reduced Cardiac Size and Function
(A and B) Time course of echocardiographic dimension changes in control and GDF11 mice. (A) Left ventricular internal diameter (diastole/systole) (LVIDd/s) and (B) posterior wall thickness (diastole/systole) (PWTd/s) measurements are shown. (C–F) Time course of changes in echocardiographic measurements of (C) left ventricle (LV) mass and cardiac function as measured by (D) stroke volume, (E) ejection fraction, and (F) fractional shortening. Horizontal lines with error bars indicate mean ± SD. Statistically significant differences are indicated at p < 0.05 (*), p < 0.01 (**), and p < 0.001 (***).
Figure 3
Figure 3. Skeletal Muscle Weight and Function Decrease with GDF11 Overexpression
(A–C) Weights of the left hind limb (A) gastrocnemius, (B) quadriceps, and (C) tibialis muscles taken at sacrifice were reported as percentages of initial body weight (IBW). Muscle weights of normal mice (n=4) taken at day 13 are shown to the left of the dashed vertical line, and those of control and GDF11 mice at day 10 (n=5 and n=8, respectively) and at day 13 (n=5 and n=7, respectively) are compared to the right of the line. Horizontal lines with error bars indicate mean ± SEM. (D) Grip strength measurements at day 10 and 13. Each data point is an average of 3 separate measurements in each mouse. Horizontal lines with error bars indicate mean ± SEM. (E) Mean quadriceps myocyte fiber cross-sectional area (CSA) of normal, control, and GDF11 mice at day 13. Data are mean ± SD. (F) Histogram of quadriceps CSA for normal, control, and GDF11 mice at day 13. (G) Laminin staining (10x magnification, 100 μm scale bar) of left hind limb quadriceps muscle cross-sections in normal, control, and GDF11 mice at day 13. Numerical data of mean myocyte CSA (data are mean ± SEM) and number of fibers measured are shown in table below for N=4, 4, and 5 mice for normal, control and GDF11 mice respectively. (H) Gene expression analyses of quadriceps muscle in normal (left of dashed vertical line, measured at day 13), control, and GDF11 mice at days 10 and 13. Data are represented as mean fold change ± SD. All fold changes calculated using reference gene 18S. Statistically significant differences are indicated at p < 0.05 (*), p < 0.01 (**),p < 0.001 (***), and p < 0.0001 (****).
Figure 4
Figure 4. Protein Regulatory Pathways in Quadriceps of Mice with GDF11 Overexpression Demonstrate Increased Degradation and Decreased Synthesis
(A–E) Western blotting analyses to determine activation of (A) SMAD2 signaling, (B) hypertrophy/atrophy pathways (arrowhead points to FOXO3a), (C) protein translation and synthesis, (D) autophagy, and (E) ubiquitination in normal, control, and GDF11 mice at day 13. Blots are presented on the left and protein levels quantified in graphs on the right. Horizontal lines with error bars indicate mean ± SD. Statistically significant differences are indicated at p < 0.05 (*), p < 0.01 (**), and p < 0.0001 (****).

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