Dysregulated mitochondrial Ca2+ and ROS signaling in skeletal muscle of ALS mouse model

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by motor neuron loss and prominent skeletal muscle wasting. Despite more than one hundred years of research efforts, the pathogenic mechanisms underlying neuromuscular degeneration in ALS remain elusive. While the death of motor neuron is a defining hallmark of ALS, accumulated evidences suggested that in addition to being a victim of motor neuron axonal withdrawal, the intrinsic skeletal muscle degeneration may also actively contribute to ALS disease pathogenesis and progression. Examination of spinal cord and muscle autopsy/biopsy samples of ALS patients revealed similar mitochondrial abnormalities in morphology, quantity and disposition, which are accompanied by defective mitochondrial respiratory chain complex and elevated oxidative stress. Detailing the molecular/cellular mechanisms and the role of mitochondrial dysfunction in ALS relies on ALS animal model studies. This review article discusses the dysregulated mitochondrial Ca 2+ and reactive oxygen species (ROS) signaling revealed in live skeletal muscle derived from the ALS mouse models, and a potential role of the vicious cycle formed between the dysregulated mitochondrial Ca 2+ signaling and excessive ROS production in promoting muscle wasting during ALS progression.

Recombinant human MG53 protein preserves mitochondria integrity in cardiomyocytes during ischemia reperfusion-induced oxidative stress

“…Transgenic mice with expression of mt-cpYFP provides assessment of the dynamic changes in superoxide signal from the mitochondria [15][16][17][18][19][20] Cardiomyocytes were isolated from the mt-cpYFP transgenic mice following the protocol of Wang et al [17]. The isolated cardiomyocytes were subjected to 3 hours of hypoxia and 2 hours of reoxygenation.…”

“…HL-1 cardiomyocytes (Sigma, SCC065) were cultured at low passages (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) according to established protocols [22,23]. For H2O2 damage, HL-1 cells were subjected to 300 μM H2O2 in unsupplemented Claycomb media (Sigma, 51800C) for 1 hour and recovered with either 10 µg/mL BSA or rhMG53 for 2 hours.…”

“…White scale bar = 50 μmWang et al[26] developed a novel indicator targeted to the mitochondrial matrix called circularly permuted yellow fluorescent protein (mt-cpYFP) that selectively fluoresce in the presence of O2 -, the main ROS created by the electron transport chain in the mitochondria. We have recently used this tool to study mitochondrial ROS generation in the mouse model of amyotrophic lateral sclerosis (ALS), termed "mitoFlash"[15,[18][19][20].…”

Protection from the Pathogenesis of Neurodegenerative Disorders, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Parkinson’s Diseases, through the Mitigation of Reactive Oxygen Species

“…The symptoms of Huntington's disease include cognitive impairments, movement disorders, and psychiatric disorders [47]. Amyotrophic lateral sclerosis is a serious neuromuscular disorder characterized by the loss of motor neurons and signi icant skeletal muscle wasting over a short period of time [48].…”

“…Amyotrophic lateral sclerosis is an irrev ersible neurodegenerative disorder that quickly progresses and causes the erosion of motor neurons not only within the brain but also throughout the spinal cord [192][193][194]. In addition, ALS is accompanied by the reduction and dysfunction of upper motor neurons [48,195,196]. ALS leads to the progressive but selective erosion of spinal, bulbar, and cortical motoneurons, which results in speech loss, progressive paralysis, dif iculty in swallowing, and several respiratory malfunctions.…”