Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

被引:55
作者
Ahn, Bumsoo [1 ]
Ranjit, Rojina [1 ]
Premkumar, Pavithra [1 ]
Pharaoh, Gavin [1 ,2 ]
Piekarz, Katarzyna M. [1 ,3 ]
Matsuzaki, Satoshi [1 ]
Claflin, Dennis R. [7 ]
Riddle, Kaitlyn [1 ]
Judge, Jennifer [6 ]
Bhaskaran, Shylesh [1 ]
Natarajan, Kavithalakshmi Satara [1 ]
Barboza, Erika [1 ]
Wronowski, Benjamin [2 ]
Kinter, Michael [1 ]
Humphries, Kenneth M. [1 ,2 ,5 ]
Griffin, Timothy M. [1 ,2 ,3 ,4 ,5 ]
Freeman, Willard M. [2 ,5 ]
Richardson, Arlan [2 ,4 ,5 ]
Brooks, Susan V. [6 ]
Van Remmen, Holly [1 ,2 ,4 ,5 ]
机构
[1] Oklahoma Med Res Fdn, Aging & Metab Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA
[2] Univ Oklahoma, Hlth Sci Ctr, Dept Physiol, Oklahoma City, OK USA
[3] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Ctr Neurosci, Oklahoma City, OK USA
[4] Oklahoma City VA Med Ctr, Oklahoma City, OK USA
[5] Univ Oklahoma, Hlth Sci Ctr, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK USA
[6] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
[7] Univ Michigan, Dept Surg, Sect Plast Surg, Ann Arbor, MI 48109 USA
关键词
Skeletal muscle; Mitochondria; MnSOD; Reactive oxygen species; Fibre branching; Hyperplasia; ALPHA-KETOGLUTARATE DEHYDROGENASE; PERMEABILITY TRANSITION PORE; CUZN-SUPEROXIDE-DISMUTASE; SKELETAL-MUSCLE; HYDROGEN-PEROXIDE; ATROPHY; DEFICIENCY; MICE; DYSFUNCTION; EXERCISE;
D O I
10.1002/jcsm.12375
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated. Methods We generated mice lacking skeletal muscle-specific manganese-superoxide dismutase (mSod2KO) to increase mtROS using a cre-Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction. Results The mSod2KO mice, contrary to our prediction, exhibit a 10-15% increase in muscle mass associated with an 50% increase in central nuclei and 35% increase in branched fibres (P < 0.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, in situ sciatic nerve-stimulated isometric maximum-specific force (N/cm(2)), force per cross-sectional area, is impaired by 60% and associated with increased NMJ fragmentation and size by 40% (P < 0.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by 100%, oxidized glutathione is elevated by 50%, and oxidative modifications of myofibrillar proteins are increased by 30% (P < 0.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex-II-mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (10 min vs. 2 h in wild type, P < 0.05). Conclusions Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching.
引用
收藏
页码:411 / 428
页数:18
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