| Title | Absence of physiological Ca2+ transients is an initial trigger for mitochondrial dysfunction in skeletal muscle following denervation |
| Authors | Karam, Chehade Yi, Jianxun Xiao, Yajuan Dhakal, Kamal Zhang, Lin Li, Xuejun Manno, Carlo Xu, Jiejia Li, Kaitao Cheng, Heping Ma, Jianjie Zhou, Jingsong |
| Affiliation | Rush Univ, Sch Med, Chicago, IL 60612 USA. Kansas City Univ Med & Biosci, 1750 Independence Ave, Kansas City, MO 64106 USA. Peking Univ, Inst Mol Med, Beijing, Peoples R China. Ohio State Univ, Wexner Med Ctr, 460 West 12th Ave, Columbus, OH 43210 USA. Rush Univ, Sch Med, Chicago, IL 60612 USA. Ma, JJ (reprint author), Ohio State Univ, Wexner Med Ctr, 460 West 12th Ave, Columbus, OH 43210 USA. |
| Keywords | E-C coupling Calcium imaging Calcium signaling Calcium intracellular release Denervation Mitochondria FOXO TRANSCRIPTION FACTORS SUPEROXIDE FLASHES PERMEABILITY TRANSITION CALCIUM UNIPORTER ENERGY-METABOLISM UBIQUITIN LIGASES SOLEUS MUSCLE MDX MICE ATROPHY PROTEIN |
| Issue Date | 2017 |
| Publisher | SKELETAL MUSCLE |
| Citation | SKELETAL MUSCLE.2017,7. |
| Abstract | Background: Motor neurons control muscle contraction by initiating action potentials in muscle. Denervation of muscle from motor neurons leads to muscle atrophy, which is linked to mitochondrial dysfunction. It is known that denervation promotes mitochondrial reactive oxygen species (ROS) production in muscle, whereas the initial cause of mitochondrial ROS production in denervated muscle remains elusive. Since denervation isolates muscle from motor neurons and deprives it from any electric stimulation, no action potentials are initiated, and therefore, no physiological Ca2+ transients are generated inside denervated muscle fibers. We tested whether loss of physiological Ca2+ transients is an initial cause leading to mitochondrial dysfunction in denervated skeletal muscle. Methods: A transgenic mouse model expressing a mitochondrial targeted biosensor (mt-cpYFP) allowed a real-time measurement of the ROS-related mitochondrial metabolic function following denervation, termed "mitoflash." Using live cell imaging, electrophysiological, pharmacological, and biochemical studies, we examined a potential molecular mechanism that initiates ROS-related mitochondrial dysfunction following denervation. Results: We found that muscle fibers showed a fourfold increase in mitoflash activity 24 h after denervation. The denervation-induced mitoflash activity was likely associated with an increased activity of mitochondrial permeability transition pore (mPTP), as the mitoflash activity was attenuated by application of cyclosporine A. Electrical stimulation rapidly reduced mitoflash activity in both sham and denervated muscle fibers. We further demonstrated that the Ca2+ level inside mitochondria follows the time course of the cytosolic Ca2+ transient and that inhibition of mitochondrial Ca2+ uptake by Ru360 blocks the effect of electric stimulation on mitoflash activity. Conclusions: The loss of cytosolic Ca2+ transients due to denervation results in the downstream absence of mitochondrial Ca2+ uptake. Our studies suggest that this could be an initial trigger for enhanced mPTP-related mitochondrial ROS generation in skeletal muscle. |
| URI | http://hdl.handle.net/20.500.11897/474044 |
| ISSN | 2044-5040 |
| DOI | 10.1186/s13395-017-0123-0 |
| Indexed | SCI(E) |
| Appears in Collections: | 分子医学研究所 |
