Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder involving degeneration of motor neurons and atrophy of skeletal muscle. Mutations in the superoxide dismutase (SOD1) gene are linked to most cases of inherited ALS, resulting in impaired metabolic function of the mitochondria. Currently, there is a lack of knowledge on how dysfunctional mitochondria and altered Ca signaling contribute to muscle degeneration during ALS progression. This new investigator initiated research project will test the hypothesis that """"""""during the development of ALS, action potential activity at the neuromuscular junction (NMJ) will cause local Ca overload in mitochondria compromised by the presence of mutant SOD1. This overload will further disrupt mitochondria-sarcoplasmic reticulum (SR) coupling and lead to altered Ca and reactive oxygen species (ROS) signaling. The alteration in turn will increase local Ca, reinforcing the local deficit, thus constituting a primary event in the pathophysiology of ALS muscle"""""""". The central theme of our studies is to develop a comprehensive understanding of the cellular mechanism that contributes to the progressive decline in mitochondria-SR coupling leading to the compromised Ca homeostatic capacity of ALS muscle. We anticipate that information obtained from our research will apply to other neuromuscular diseases, such as aging, diabetes, Parkinson's disease and others, where altered Ca signaling and intracellular oxidative stress are linked to dysfunctional muscle contractility and altered motor neuron communication.
In Aim 1, we propose to quantify the mitochondrial contribution to local control of SR Ca signaling, and use this quantification to evaluate how defective mitochondria-SR coupling contributes to progression of muscle wasting in ALS. By characterizing the changes in Ca signaling and mitochondrial function in skeletal muscle at different stages of ALS progression, our studies should provide a mechanistic understanding of how local control of SR Ca signaling is altered by mitochondria, how this process is altered in ALS muscle and what is the influence of axonal withdrawal in disrupting SR-mitochondria coupling leading to the progressive decline of muscle function in ALS.
In Aim 2, we propose to use localized mitochondrial superoxide (O2-) FLASH signal as an index for mitochondrial metabolic function in ALS muscle, and to examine the effect of denervation on the interplay between mitochondria-SR in controlling intracellular Ca release and local O2- levels during the progression of muscle atrophy in ALS. These studies will reveal the role of localized coupling between Ca and O2- production in muscle physiology, and establish the cellular mechanism(s) that contribute to NMJ remodeling and the progressive development of muscle pathology in ALS.
Amyotrophic lateral sclerosis (ALS), often referred to as Lou Gehrig's Disease, is a progressive neuromuscular disorder that involves loss of nerve cells in the brain and the spinal cord, and atrophy of skeletal muscle. It is generally believed nerve degeneration precedes and then causes the muscle atrophy. We ask if muscle is also involved in the disease onset and progression. Muscle cells use Calcium (Ca) as a messenger to control their contraction activity, while excessive elevation of Ca inside the cell will cause cell death. We have discovered uncontrolled hyperactive Ca signals in muscle cells of ALS transgenic mouse model. Two major organelles are involved for the tight control of the intracellular Ca level, the sarcoplasmic reticulum (SR)-the site of Ca storage in muscle cells, and mitochondria-the power house that can also produce detrimental oxidative stress. In this project, using state of the art molecular tools and transgenic mouse models we will aim at a comprehensive understanding of the cellular mechanism that contributes to the progressive decline in mitochondria-SR coupling that leads to the compromised Ca signaling in ALS muscle. It is anticipated that our results will accelerate development of new means to extend muscle function of patients suffering from ALS. We also believe that information obtained from our research will be of general application to other neuromuscular diseases, such as aging, diabetes, Parkinson's disease, etc, where altered Ca signaling and intracellular oxidative stress are linked to dysfunctional properties of contractile function and neuron communication.
|Xiao, Yajuan; Karam, Chehade; Yi, Jianxun et al. (2018) ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression. Pharmacol Res 138:25-36|
|Kitase, Yukiko; Vallejo, Julian A; Gutheil, William et al. (2018) ?-aminoisobutyric Acid, l-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor. Cell Rep 22:1531-1544|
|Wang, Huan; Yi, Jianxun; Li, Xuejun et al. (2018) ALS-associated mutation SOD1G93A leads to abnormal mitochondrial dynamics in osteocytes. Bone 106:126-138|
|Xu, Xiulong; Sun, Jing; Song, Ruilong et al. (2017) Inhibition of p70 S6 kinase (S6K1) activity by A77 1726, the active metabolite of leflunomide, induces autophagy through TAK1-mediated AMPK and JNK activation. Oncotarget 8:30438-30454|
|Chen, Ken; Xu, Zaicheng; Liu, Yukai et al. (2017) Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury. Sci Transl Med 9:|
|Zhang, Yong-Guo; Wu, Shaoping; Yi, Jianxun et al. (2017) Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis. Clin Ther 39:322-336|
|Yao, Yonggang; Zhang, Bo; Zhu, Hua et al. (2016) MG53 permeates through blood-brain barrier to protect ischemic brain injury. Oncotarget 7:22474-85|
|Zhou, Jingsong; Dhakal, Kamal; Yi, Jianxun (2016) Mitochondrial Ca(2+) uptake in skeletal muscle health and disease. Sci China Life Sci 59:770-6|
|Zhou, Jingsong; Yi, Jianxun; Bonewald, Lynda (2015) Muscle-Bone Crosstalk in Amyotrophic Lateral Sclerosis. Curr Osteoporos Rep 13:274-9|
|Zhu, Ke; Yi, Jianxun; Xiao, Yajuan et al. (2015) Impaired bone homeostasis in amyotrophic lateral sclerosis mice with muscle atrophy. J Biol Chem 290:8081-94|
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