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Zhang 2015 Abstract MiPschool Greenville 2015

From Bioblast
Skeletal muscle NAMPT overexpression prevents mitochondrial dysfunction during hindlimb unloading induced muscle atrophy.


Zhang X, Gabriel M, Goodpaster BH, Gardell SJ, Smith SR, Coen PM (2015)

Event: MiPschool Greenville 2015

Periods of skeletal muscle disuse lead to mitochondrial dysfunction, which in turn contributes to muscle atrophy and weakness [1]. While the mechanisms responsible for metabolic dysfunction during muscle disuse have yet to be elucidated, recent evidence has implicated members of the sirtuin (SIRT) family [2,3]. In particular, SIRT1 and 3 regulate mitochondrial biogenesis, lipid oxidation, and reactive oxygen species (ROS) emission. Nicotinamide adenine dinucleotide (NAD+) is an obligatory co-substrate for sirtuins [4]. Brisk intracellular consumption of NAD+ is counterbalanced by its continued synthesis in part due to the action of nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting enzyme in the NAD+ salvage pathway. We hypothesized that elevated NAD+ in skeletal muscle during muscle disuse would maintain mitochondrial function and preserve muscle mass.

To test this hypothesis, male C57BL/6 mice with muscle specific NAMPT transgenic overexpression (NamptTG) and non-transgenic (NT) littermates were divided into four groups: TG (TG-U) and NT (NT-U) 10 days of unloading, and TG (TG-C) and NT (NT-C) 10 days of control. Following the treatments, mice were sacrificed by CO2 asphyxiation. Hind limb muscle groups were harvested, weighed and snap frozen. Permeabilized fiber bundles were prepared from the right soleus to measure mitochondrial respiration (Oroboros Oxygraph-2k), H2O2 emission and calcium retention capacity (CRC).

Food intake and body weight did not change over the 10-day treatments. A similar degree of soleus atrophy was observed in NT and NamptTG mice following hindlimb unloading. While mitochondrial dysfunction was evident in the soleus of NT-U mice, NamptTG-U mice were protected from the negative effects of unloading. Respiration (71.8%, P = 0.0017) and CRC (81.7%, p = 0.039) were lower in the NT-U compared to NamptTG-U. H2O2 emission increased to a greater degree in the NT-U compared to NamptTG-U (119.4%, p =0.023).

These studies reveal for the first time that increased NAMPT (~8-fold) and NAD+ (~1.7-fold) in skeletal muscle prevented the loss of mitochondrial function by disuse, independent of muscle atrophy. Future studies should focus on whether NamptTG also preserves insulin sensitivity with unloading and capacity to recover (hypertrophy) with reloading.

β€’ O2k-Network Lab: US FL Orlando Goodpaster BH, US FL Orlando Translational Research Institute

Labels: MiParea: Respiration, mt-Biogenesis;mt-density 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

HRR: Oxygraph-2k, Ca  Event: Poster 


1-Translational Research Inst Metabolism Diabetes, Florida Hospital; 2-Diabetes Obesity Research Center, Sanford-Burnham-Prebys Med Discovery Inst, Orlando, FL, USA. -

References and acknowledgements

  1. Powers SK, Wiggs MP, Duarte JA, Zergeroglu AM, Demirel HA (2012) Mitochondrial signaling contributes to disuse muscle atrophy. Am J Physiol Endocrinol Metabol 303:E31-9.
  2. Lee D, Goldberg AL. (2013) SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth. J Biol Chem. 288:30515-26.
  3. Lin L, Chen K, Abdel Khalek W, Ward JL 3rd, Yang H, Chabi B, Wrutniak-Cabello C, Tong Q (2014) Regulation of skeletal muscle oxidative capacity and muscle mass by SIRT3. PloS one 9:e85636.
  4. Canto C, Menzies KJ, Auwerx J (2015) NAD metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metabol 22:31-53.

Grant Support: This research was supported a grant from National Institute of Aging (AG044437-PMC)