Objective 1: Determine the effect of NMN on mitigating unloading-induced musculoskeletal loss. We will use hindimb suspension (HS) in mice to simulate microgravity-induced muscle unloading. Our hypothesis is NMN administration during unloading mitigates muscle atrophy, bone loss, and functional impairment. We will also investigate if NMN alleviates slow-to-fast fiber type shift caused by muscle unloading, which significantly reduces fatigue resistance of the slow-twitch muscles.
Objective 2: Determine if NMN improves the effectiveness of exercise during unloading. As an exercise mimetics, NAD+ promotes the beneficial effects of exercise by activating SIRT1. We propose that raising NAD+ levels during exercise confers additive benefits than does exercise alone. We will test if SIRT1 overexpression or NMN administration augment the effectiveness of exercise and further mitigate musculoskeletal loss.
Objective 2. Determine if NMN improves the effectiveness of exercise during unloading. Physical exercise is still the most effective countermeasure to mitigate musculoskeletal loss in space (Petersen et al., 2016). Functioning as an exercise mimetics, NMN increases NAD+ levels and activates SIRT1 in skeletal muscle (Fan and Evans, 2017). SIRT1 is not only a critical gene regulating anabolic and catabolic pathways in the muscle (see Objective 1), but involved in regulating mitochondria function and biogenesis, a dictator of energy production and overall condition of the muscle (Gomes et al., 2013; Price et al., 2012). Moreover, our accepted work in Cell showed that SIRT1 is required for exercise-induced neovascularization in skeletal muscle (Das et al., Cell. Accepted). We found that NMN intake combined with training could further increase the capillary density in quadriceps in mice, suggesting a synergistic effect between raising NAD+ levels and exercise. In this objective, we will first test if SIRT1 activity is a factor that determines the exercise outcomes. Based on our preliminary results, we will further determine if NMN improves the effectiveness of exercise countermeasures on preserving muscle mass, strength, and endurance during unloading.
This experiment is currently in progress. Results will be available at the conclusion of the study.
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