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BDA-410 Treatment Reduces Body Weight and Fat Content by Enhancing Lipolysis in Sedentary Senescent Mice.

ABSTRACT: Loss of muscle mass and force with age leads to fall risk, mobility impairment, and reduced quality of life. This article shows that BDA-410, a calpain inhibitor, induced loss of body weight and fat but not lean mass or skeletal muscle proteins in a cohort of sedentary 23-month-old mice. Food and water intake and locomotor activity were not modified, whereas BDA-410 treatment decreased intramyocellular lipid and perigonadal fat, increased serum nonesterified fatty acids, and upregulated the genes mediating lipolysis and oxidation, lean phenotype, muscle contraction, muscle transcription regulation, and oxidative stress response. This finding is consistent with our recent report that lipid accumulation in skeletal myofibers is significantly correlated with slower fiber-contraction kinetics and diminished power in obese older adult mice. A proteomic analysis and immunoblot showed downregulation of the phosphatase PPP1R12B, which increases phosphorylated myosin half-life and modulates the calcium sensitivity of the contractile apparatus. This study demonstrates that BDA-410 exerts a beneficial effect on skeletal muscle contractility through new, alternative mechanisms, including enhanced lipolysis, upregulation of "lean phenotype-related genes," downregulation of the PP1R12B phosphatase, and enhanced excitation-contraction coupling. This single compound holds promise for treating age-dependent decline in muscle composition and strength.

SUBMITTER: Pereyra AS

PROVIDER: S-EPMC5861946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction/Purpose: Physical activity and sedentary time may associate with physical fitness and body composition. Yet, there exists some observational studies that have investigated the associations of device-based measures of sedentary time and physical activity (PA) with cardiorespiratory fitness (CRF) and body composition but associations with muscular fitness (MF) are less studied. Methods: Objective sedentary time and physical activity was measured by a hip worn accelerometer from 415 young adult men (age: mean 26, standard deviation 7 years). Cardiorespiratory fitness (VO2max) (CRF) was determined using a graded cycle ergometer test until exhaustion. Maximal force of lower extremities was measured isometrically and lower body power was assessed using standing long jump (MF). Body composition was determined with bioimpedance method. Single and compositional approach was used in regression analysis. Results: Mean sedentary time was 707 (standard deviation 133) minutes per day (77 ± 8% of the wear time). Volumes of all PA intensities were positively associated with CRF and associations showed linearly increasing magnitudes with higher intensities in single regression models adjusted for age and smoking (p < 0.001). Similarly, PA intensities were positively associated with lower body MF, however, with weaker associations (p < 0.005). After further adjustment for resistance training, the associations remained significant. The associations of the relative distribution of time within sedentary behavior (SB), light intensity PA (LPA) and moderate-to-vigorous PA (MVPA) behaviors as a whole with using compositional analysis further revealed that within the composition MVPA and SB were positively associated with CRF and MF (p < 0.001), while LPA was not. In addition, within the composition, accumulated PA bouts lasting more than 3 min were consistently associated with CRF and MF, and with all body composition variables (p < 0.001), while sedentary time was associated with body fat percentage (p < 0.001). Conclusion: Promoting physical activity and reducing sedentary time may have positive influence on physical fitness and body fat content, and thereby may offer positive health effects. Physical activity of higher intensities may offer greater benefits.

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BDA-410 Treatment Reduces Body Weight and Fat Content by Enhancing Lipolysis in Sedentary Senescent Mice.

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