DO Hold your Breath? Hypoxia Induces Heart Regeneration

Regeneration of healthy heart tissue to repair and aid the failing myocardium is of great interest to human health and longevity.  Approaches to heart tissue repair have included mechanical assist devices, gene therapy, and cell transplantation.   Since the mammalian heart is one of the least regenerative organs, cardiac muscle injury is a leading cause of death and disability worldwide.

 

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The neonatal heart is capable of regenerating lost myocardium, mediate primarily through the proliferation of pre-existing heart cells.  Cycling adult cardiomyocytes are hypoxic, thereby protected from oxidative DNA damage. Mitochondrial-derived reactive oxygen species (ROS) are culprit in oxidative stress, causing cardiomyocyte cell cycle arrest through ROS-induced oxidative DNA damage.  Up until recently, it was not known whether changes in ambient oxygen could affect cardiomyocyte cell cycle in adult mammals.  Accordingly, researchers from the University of Texas Southwestern Medical Center in Dallas hypothesized that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals (1).

Nakada et al. exposed B6 mice to low oxygen tension for over two weeks (1).   There were a greater number of heart cells and the hearts were larger in hypoxic mice than in normoxic mice.  The gradual reduction of inspired oxygen downregulated mitochondrial metabolism and ROS production in adult cardiomyocytes.  Functional recovery in mice with myocardial infarction (MI) was significantly better in hypoxic animals (1).

Extending hypoxia to 3 weeks resulted in greater mortality in hypoxic MI animals, yet surviving hypoxic animals still had better preserved cardiac function than normoxic MI animals.  The authors suggest that the hypoxic conditions might have been rough on the animals [e.g., ”in pursuit of more tolerable hypoxic conditions, we tested mild  hypoxia (10% oxygen)…”] (1).  The data indicate that food consumption was halved in hypoxic animals.  Remarkably, body weight was hardly affected.

The ECGenie can been used to monitor the heart rate of hypoxic animals vs. normoxic animals, as another metric of the metabolic effects of hypoxia and recovery from MI.  The heart rate of active adult B6 mice at rest is ~725 bpm, rising above 800 bpm with activity, and falling to ~450 bpm while resting.  The ECGenie readily shows ST segment changes with ischemia and infarction.   It is interesting to consider the present study in different strains of mice with different baseline metabolics (2), or mice treated with sympathetic and cholinergic compounds (3).   Age and blood flow regulation are also known to affect survival under hypoxia.  The ECGenie readily reports ECG changes in newborn and aged mice, in normoxic and hypoxic conditions, at baseline and following sympathetic and cholinergic drugs.

The elegant study performed by Nakada et al. demonstrates that the regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine (1).

References:

  1. Nakada Y et al. Hypoxia induces heart regeneration in adult mice. Nature. 2017 Jan 12;541(7636):222-227.
  2. Campen et al. Phenotypic variation in cardiovascular responses to acute hypoxic and hypercapnic exposure in mice. Physiol Genomics. 2004 Dec 15;20(1):15-20.
  3. Scremin et al. Survival under hypoxia. Age dependence and effect of cholinergic drugs. Stroke. 1980 Sep-Oct;11(5):548-52.

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ECGenie on Inauguration Day: Crowd Size, and Alternative Facts

Researchers across America, and across the world, have historically been very interested in recording the ECG of awake laboratory animals, to query how genes, diseases, and drugs might affect or improve human hearts and health.

There is growing awareness that the ECG of a conscious laboratory mouse, replete with active autonomic nervous system modulation, is more informative and translatable to human health than the ECG from an anesthetized subject. Proponents of telemetry will advocate that ECG in awake lab animals requires surgically implanted ECG transmitters, and misleadingly claim there is no alternative. Facts are abundant, however, reflected through numerous scientific publications, that the ECGenie provides comparable ECG data, in larger numbers of animals, more humanely, at far less cost, and at a much faster speed. These facts and features are hugely beneficial to pre-clinical studies.

We non-invasively recorded the ECG in 3 awake mice with the ECGenie during President Trump’s ~16 minute inaugural address . The instrumentation is shown in Figure 1; representative data from the brief ECG recordings are shown in the right panel.

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Getting CRISPR!

untitled1Neuromuscular and cardiovascular diseases are active areas for application of CRISPR-Cas9 targeting to query the role of targeted mutations in recapitulating or correcting features of the analogous human genetic defects in vivo in live animals.

Recently, porcine zygote injection with Cas9/sgRNA resulted in the generation of a piglet with muscular dystrophy (1). The piglet exhibited degenerative skeletal and cardiac muscle, potentially modeling symptoms of human muscular dystrophy (1). The CRISPR-Cas9 system has also been used to generate a rat model of Duchenne muscular dystrophy (2). Mutated rats exhibited a decline in muscle strength, and the emergence of degenerative phenotypes in skeletal muscle and heart. The mutations were heritable by the next generation, and F1 male rats exhibited similar phenotypes in their skeletal muscles (2).  In contrast, Exon 23 deletion by CRISPR-Cas9 in the dystrophin-deficient mdx mouse resulted in expression of the dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, and significant enhancement of muscle force. (3) Others too have demonstrated that genome editing partially restores dystrophin expression in mice with muscular dystrophy (4, 5).
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Clowning Around

clowning_around_graphicEither you are intrigued with the hysteria regarding clown sightings, or eager to learn the latest about the presidential election. In either case, please read on. Though clowns hope to make us laugh, they sometimes instill fear; fear and laughter, stress and joy, greatly affect our cardiovascular health. Many adults, moreover, are finding the presidential election in the United States entertaining, yet stressful.

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A New Lead for Better Lab Animal Welfare

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Quite possibly you are already using the ECGenie in your pre-clinical research, to non-invasively monitor the heart of your awake laboratory animals. We are quite proud of this elegant device to non-invasively study the heart of conscious rodents, and are always thinking of ways to improve and extend the technology.

We have recently patented a novel extension to the ECGenie methodology that significantly increases the speed at which you can record the ECG, while improving the quality of the ECG signals themselves. We have packaged our recent patented technology into a newly revamped ECGenie lead plate.

The new and improved ECGenie lead plates (US Patent #8,694,086) speed up the recording of ECG data by more than 30% faster than the legacy foot plate electrodes. In our hands, the stability and quality of the ECG signals also appear to be greatly enhanced. With this new lead plate design, you will increase your research productivity and efficiency.

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CALAS Toronto 2016

Canadian Association for Laboratory Animal Science    Annual Meeting

 

Much like the Toronto Blue Jay’s performances, CALAS 2016 was a grand slam. A great venue, great colleagues, and cutting edge research all contributed to the big win for the 55th Annual Symposium held at the Fairmont Hotel in Toronto, earlier this baseball season. Now half way through the season, the Blue Jays are tied with our own Boston Red Sox and only a few games back from 1st place, and plans for the next CALAS symposium in Calgary for June 2017 are already in progress. We are all winners with such dedication to doing our best.

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The Bubble Man’s Walk to Bermuda – Time for Serious Gait Analysis

Mouse Specifics, Inc. is serious about providing a useful quantitative instrument to the research community to advance better understanding of animal models of human movement disorders. DigiGait is the most widely published treadmill gait analysis system available . The ability to walk and run is coveted by humans. In particular patients with Parkinson’s disease, multiple sclerosis, stroke, and spinal cord injury all hope to maintain or regain their mobility.

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DigiGait – chillax, and see how they run!

European researchers lead the way in advocating for the health and well-being of laboratory animals. These efforts are improving laboratory animal welfare worldwide, while driving greater awareness of refinement, replacement, and reduction of in vivo studies. Laboratory animals are used to model many human conditions that are characterized by movement disorders. Parkinson’s disease, multiple sclerosis, and arthritis, for example, disturb gait in humans; research scientists study the gait of animal models of these disorders to better understand and treat the human problems. What is the best way to comprehensively study their gait, without stress, and yet honor their great contribution to advances in improving health and well-being?

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Hoop Dreams

Hoop_dreams_blog_imageMouse Specifics, Inc. is a proud sponsor of the FSH Society Boston Basketball Tournament March 21, 2016, at the TD Garden.

The FSH Society is a nonprofit, patient-driven organization supporting research and education for facioscapulohumeral muscular dystrophy (FSHD), one of the most prevalent forms of muscular dystrophy.  Founded in 1991 by two individuals with FSHD, Steve Jacobsen and Daniel Perez, the FSH Society is the world’s largest and most progressive grassroots network of patients, families, clinicians and research activists. Among the most prevalent of the muscular dystrophies, FSHD affects an estimated 870,000 people worldwide.

Basic research in animal models is crucial to understanding and treating FSHD.  Mouse Specifics, Inc. technology has been used in discoveries in numerous preclinical models of neuromuscular disorders, including Duchenne muscular dystrophy, Limb Girdle Muscular Dystrophy, and Spinal Muscular Atrophy.

Please consider donating to the FSH to fund important research!

Come to TD Garden to watch the Mouse Specifics team dazzle with our basketball skills on March 21!

Any FSH-funded researchers with a mouse model relevant to FSHD are welcome to send us animals for DigiGait Imaging or ECGenie monitoring, as a courtesy to help advance your research.

Rocky Balboa

rockSylvester Stallone, the creative genius behind the universally known and beloved boxer Rocky Balboa, was recently honored with the Golden Globe for the best supporting actor in his seventh “Rocky” film Creed.   Mr. Stallone may yet again be awarded an Academy Award [Rocky won Best Picture in 1977], in now-realized recognition of his talents as an actor.

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