Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS

Martin, Lee J.; Niedzwiecki, Mark; Wong, Margaret

doi:10.3390/cells10020320

Cited by 4 publications

(3 citation statements)

References 55 publications

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“…Sirtuin6 is also cold-inducible and regulates thermogenesis [ 102 ]. In this regard, Sirtuin6 is of interest because repetitive periodic whole-body hypothermia can extend the lifespan of ALS mice [ 103 ]. hSOD1 mus -G37R mice also had hypermethylation of mex3d gene.…”

Section: Discussionmentioning

confidence: 99%

Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic

Martin

Adams

Niedzwiecki

et al. 2022

Cells

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Amyotrophic lateral sclerosis (ALS) is a fatal disease. Skeletal muscles and motor neurons (MNs) degenerate. ALS is a complex disease involving many genes in multiple tissues, the environment, cellular metabolism, and lifestyles. We hypothesized that epigenetic anomalies in DNA and RNA occur in ALS and examined this idea in: (1) mouse models of ALS, (2) human ALS, and (3) mouse ALS with therapeutic targeting of DNA methylation. Human superoxide dismutase-1 (hSOD1) transgenic (tg) mice were used. They expressed nonconditionally wildtype (WT) and the G93A and G37R mutant variants or skeletal muscle-restricted WT and G93A and G37R mutated forms. Age-matched non-tg mice were controls. hSOD1 mutant mice had increased DNA methyltransferase enzyme activity in spinal cord and skeletal muscle and increased 5-methylcytosine (5mC) levels. Genome-wide promoter CpG DNA methylation profiling in skeletal muscle of ALS mice identified hypermethylation notably in cytoskeletal genes. 5mC accumulated in spinal cord MNs and skeletal muscle satellite cells in mice. Significant increases in DNA methyltransferase-1 (DNMT1) and DNA methyltransferase-3A (DNMT3A) levels occurred in spinal cord nuclear and chromatin bound extracts of the different hSOD1 mouse lines. Mutant hSOD1 interacted with DNMT3A in skeletal muscle. 6-methyladenosine (6mA) RNA methylation was markedly increased or decreased in mouse spinal cord depending on hSOD1-G93A model, while fat mass and obesity associated protein was depleted and methyltransferase-like protein 3 was increased in spinal cord and skeletal muscle. Human ALS spinal cord had increased numbers of MNs and interneurons with nuclear 5mC, motor cortex had increased 5mC-positive neurons, while 6mA was severely depleted. Treatment of hSOD1-G93A mice with DNMT inhibitor improved motor function and extended lifespan by 25%. We conclude that DNA and RNA epigenetic anomalies are prominent in mouse and human ALS and are potentially targetable for disease-modifying therapeutics.

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Section: Discussionmentioning

confidence: 99%

Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic

Martin

Adams

Niedzwiecki

et al. 2022

Cells

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“… 26 ). Multiple studies have observed alterations in skeletal muscle metabolic pathways, including altered expression of mitochondrial uncoupling proteins 27 , 28 in mouse models and human biopsies associated with modulation of metabolic flexibility (i.e. the balance between the use of glucose and fatty acids as a fuel substrate).…”

Section: Muscle Autonomous Phenotype In Alsmentioning

confidence: 99%

Skeletal muscle in amyotrophic lateral sclerosis

Shefner

Musarò

Ngo

et al. 2023

Brain

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Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other MN diseases and draw perspectives for future research and treatment.

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“…In addition to the review articles, this Special Issue also contains three papers reporting original research relating to the PT. In a mouse model of ALS, Martin et al report that the therapeutic efficacy of mild whole-body hypothermia is at least partly linked to the inactivation of the mPTP [ 6 ]. Readnower et al used a genetic model of mPTP inhibition—mice lacking the CypD encoding gene Ppif —to establish that the mPTP is an important drug target in protection against traumatic brain injury [ 7 ].…”

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confidence: 99%