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. 2016 Apr 1;12(5):617-30.
doi: 10.7150/ijbs.13525. eCollection 2016.

Modeling Energy Dynamics in Mice With Skeletal Muscle Hypertrophy Fed High Calorie Diets

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Free PMC article

Modeling Energy Dynamics in Mice With Skeletal Muscle Hypertrophy Fed High Calorie Diets

Nichole D Bond et al. Int J Biol Sci. .
Free PMC article

Abstract

Retrospective and prospective studies show that lean mass or strength is positively associated with metabolic health. Mice deficient in myostatin, a growth factor that negatively regulates skeletal muscle mass, have increased muscle and body weights and are resistant to diet-induced obesity. Their leanness is often attributed to higher energy expenditure in the face of normal food intake. However, even obese animals have an increase in energy expenditure compared to normal weight animals suggesting this is an incomplete explanation. We have previously developed a computational model to estimate energy output, fat oxidation and respiratory quotient from food intake and body composition measurements to more accurately account for changes in body composition in rodents over time. Here we use this approach to understand the dynamic changes in energy output, intake, fat oxidation and respiratory quotient in muscular mice carrying a dominant negative activin receptor IIB expressed specifically in muscle. We found that muscular mice had higher food intake and higher energy output when fed either chow or a high-fat diet for 15 weeks compared to WT mice. Transgenic mice also matched their rate of fat oxidation to the rate of fat consumed better than WT mice. Surprisingly, when given a choice between high-fat diet and Ensure® drink, transgenic mice consumed relatively more calories from Ensure® than from the high-fat diet despite similar caloric intake to WT mice. When switching back and forth between diets, transgenic mice adjusted their intake more rapidly than WT to restore normal caloric intake. Our results show that mice with myostatin inhibition in muscle are better at adjusting energy intake and output on diets of different macronutrient composition than WT mice to maintain energy balance and resist weight gain.

Keywords: Computational modeling; energy balance; fat oxidation; food intake; high-fat diet; myostatin; obesity; skeletal muscle hypertrophy..

Conflict of interest statement

Competing Interests: Under a licensing agreement between Pfizer and the Johns Hopkins University, A.C.M. is entitled to a share of royalty received by the University on sales of the factor described in this paper. The terms of these arrangements are being managed by the University in accordance with its conflict of interest policies. All other authors have no competing interests.

Figures

Figure 1
Figure 1
Feeding regimens. (A) Muscle-DN mice were fed chow, HF diet or HF diet plus Ensure® for 15 weeks. (B) MSTN KO mice were fed chow for 21 days, HF diet for 14 days, then returned to chow for 14 days. Body composition was determined weekly starting at time 0 for all mice. Chow, NIH-31 diet; HF, 59% kcal from fat, Bio-Serv.
Figure 2
Figure 2
Body composition of Muscle-DN mice fed chow, HF (59% fat) diet or HF (59% fat) diet plus Ensure®. (A) Body weight (BW), (B) lean mass and (C) fat mass were measured weekly for 15 weeks beginning at ~9 weeks of age. Chow, n = 6-7; HF, n = 5-8 per group; HF + Ensure®, n = 5-6 per group. *P < 0.01; **P < 0.001 between genotypes on the same diet by repeated measures ANOVA.
Figure 3
Figure 3
Dynamic changes in calculated energy balance of Muscle-DN mice. (A) Energy input and (B) energy output in Muscle-DN mice fed chow, HF (59% fat) diet or HF (59% fat) diet plus Ensure®. Note that energy output is lower than input for WT mice, particularly on HF diets. (C) Energy balance (output subtracted from input). Note that Muscle-DN mice have close to zero energy balance on chow and HF diets, while WT mice have a more positive energy balance than Muscle-DN mice on all diets especially in the first 7 weeks. Average weekly energy intake (from direct measurements) was analyzed by repeated measures ANOVA which showed that Muscle-DN mice consumed greater calories than WT mice on chow (P = 0.013) or HF diet (P = 0.024) but not HF plus Ensure® diets (P = 0.65).
Figure 4
Figure 4
Dynamic changes in calculated fat energy utilization of Muscle-DN mice. (A) Fat intake was calculated from the percent energy from fat for each diet and fat oxidation was calculated by the computational model. Note that fat oxidation matches intake more closely for Muscle-DN mice than WT mice. (B) RQ compared to FQ. The FQ shown is the average over the 15-week time course. The FQ for the HF plus Ensure® groups are different between genotypes because of the differences in HF versus Ensure® intake (see Figure 4). RQ > FQ indicates glucose utilization and weight gain.
Figure 5
Figure 5
Nutrient intake of HF plus Ensure® diet in Muscle-DN mice. (A) Raw caloric intake by dietary source, 59% HF diet or Ensure®, from data used for computational modeling of intake shown in Figure 2A. (B) Total, carbohydrate, fat or protein caloric intake from combined HF plus Ensure® diets. Note that although total intake is similar, mutant mice consume relatively more calories from Ensure® and less from HF diet than do WT mice. This causes a difference in carbohydrate and fat intake between genotypes. n = 5-6 per group. Statistical significance by repeated measures ANOVA between genotypes for total HF or Ensure® intake (A) as indicated or for macronutrient intake (B) where *P < 0.05 and **P < 0.01.
Figure 6
Figure 6
Rapid adaptation to dietary change by Muscle-DN mice. (A) Daily caloric intake in Muscle-DN or WT mice before, during and after switching to Ensure® diet alone for 11 days (days 15-25). (B) Daily caloric intake in a separate group of mice switched to 45% HF diet for 10 days followed by HF diet plus chow for 4 days (days 17-30), chow (days 31-125), Ensure® plus chow for 2 days (days 126-127), 59% HF diet for 7 days (days 148-154) and switched back to chow. (C) Intake by diet the day before, during and after simultaneous feeding of 45% HF diet and chow diet as indicated by day (days 26-31) in panel B. (D) Intake by diet the day before, during and after simultaneous feeding of Ensure® and chow diet as indicated by day (days 125-128) in panel B. Gray highlight designates the time period when two diets were supplied simultaneously. Dashed lines demarcate single Ensure® or HF diet. H+C: 45% HF plus chow; E+C: Ensure® plus chow; HF 59%: 59% HF diet. n = 5-7 per group. Statistical significance between genotypes by student's t test of the daily average intake during an indicated diet interval; *P < 0.05, **P < 0.01.
Figure 7
Figure 7
MSTN KO energy intake and computational analysis. (A) Daily caloric intake in KO or WT mice before, during and after switching to 59% HF diet for 14 days (days 22-35). (B) Body weight, lean and fat mass during diet changes. (C) Calculated energy intake, output and balance, and fat intake, oxidation and RQ in WT and MSTN KO mice during diet changes. n = 8-9 per group. Statistical significance between genotypes by student's t test of the daily average intake during an indicated diet interval (A) or by repeated measures ANOVA for body composition measured over time (B); *P < 0.05, **P < 0.01 and **P < 0.001.
Figure 8
Figure 8
Energy intake differences in Muscle-DN mice fed chow. (A) Cumulative caloric intake over 4 weeks. (B) 24-hr caloric refeeding intake after a 24-hr fast as a percent of normal 24-intake. (C) 24-hr caloric intake as a percent of normal intake after a 24-hr fast and OEA injection. A and B, n = 10-11 per group; C, n = 6 per group. Statistical significance by student's t test is indicated.

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