Okayama University


Okayama University Medical Research Updates (OU-MRU) Vol.76

February 12, 2020

Source: Okayama University (JAPAN), Public Relations Division
For immediate release: 12 February 2020
Okayama University research: The molecular pathogenesis of muscular dystrophy-associated cardiomyopathy

(Okayama, 12 February) In a study recently published in Nature Communications scientists at Okayama University describe the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy.

Heart failure is the major cause of death for muscular dystrophy patients; however little is known for the molecular mechanism of muscular dystrophy-associated cardiomyopathy. In this study, A research team spearheaded by Senior Lecturer KATANOSAKA Yuki at Okayama University demonstrate for the first time the cellular and molecular pathomechanisms of muscular dystrophy-associated cardiomyopathy using mouse models of Fukuyama muscular dystrophy with a deficiency for the fukutin gene (Fktn), which encodes a Golgi-based ribitol-phosphate transferase that catalyzes the biosynthesis of tandem ribitol-phosphate structure on α- dystroglycans (DG). As DG and proteins of the dystrophin–glycoprotein complex provide structural support for the sarcolemma in muscle tissue, a loss of membrane fragility was thought to be a cause for cardiac dysfunction in these diseases collectively known as α-DGpathies. However, their data show that cardiac dysfunction in muscular dystrophy-associated cardiomyopathy occurs at the cellular cardiomyocyte level.

In this study, although cardiac Fktn elimination markedly reduced α-DG glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. Younger Fktn-deficient mice show a vulnerability to hemodynamic stress conditions via impaired compensative hypertrophic response of cardiomyocytes. Adult Fktn-deficient mice exhibit altered cardiac morphology and dysfunction, suggesting that FKTN is critical for maintaining contractile function of individual cardiomyocytes.

In addition, the team show that acute Fktn-elimination causes the disordered Golgi-microtubule network in myocytes. Finally, the team show that treatment with colchicine (an FDA-approved drug for the treatment of familial Mediterranean fever) improved cardiac dysfunction of Fktn-deficient hearts via the recovery of myocyte shortening, which may open a new avenue for therapeutic strategies.

Muscular dystrophy and heart failure: Muscular dystrophy is a genetic condition that results in debilitating muscle weakness from childhood. Symptoms range from difficulty with walking and running, frequent falls, and muscle stiffness to extreme pain. Although there are various types of muscular dystrophy, Fukuyama Congenital Muscular Dystrophy (FCMD), the second most prevalent in Japan, typically leads to cardiac and neurologic issues. FMCD results from a genetic mutation leading to loss of the fukutin protein.

Heart muscles: The heart muscles make up the walls of the heart and are responsible for it beating rhythmically. Damage to these muscles can result in heart attacks, arrythmias (irregular heartbeats), and heart failure. Proper myocyte structure and intracellular Ca2+ handling are important factors for healthy hearts. Microtubule are filaments required for the myocytes proper structure. The disorganization of microtubule induces the altered Ca2+ homeostasis in myocytes. In turn, golgi bodies are required for maintenance of the microtubule structure.

Yoshihiro Ujihara, Motoi Kanagawa, Satoshi Mohri, Satomi Takatsu, Kazuhiro Kobayashi, Tatsushi Toda, Keiji Naruse, Yuki Katanosaka. Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure. Nature Communications, (2019) 10:5754.
DOI : 10.1038/s41467-019-13623-2
Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure | Nature Communications

Reference (Okayama Univ. OU-MRU): Assistant Professor KATANOSAKA’s team
OU-MRU Vol.4:Cardiac mechanosensitive integrator
OU-MRU Vol.26:Protein for preventing heart failure

Correspondence to
Senior Lecturer KATANOSAKA Yuki, Ph.D.
Department of Cardiovascular Physiology, Graduate
School of Medicine, Dentistry and Pharmaceutical
Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku,
Okayama 700-8558, Japan
E-mail: ytanigu(a)md.okayama-u.ac.jp
For inquiries, please contact us by replacing (a) with the @ mark.

Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University

Further information
Okayama University
1-1-1 Tsushima-naka , Kita-ku , Okayama 700-8530, Japan
Public Relations Division
E-mail: www-adm(a)adm.okayama-u.ac.jp
For inquiries, please contact us by replacing (a) with the @ mark.

Website: //www.okayama-u.ac.jp/index_e.html
Okayama Univ. e-Bulletin: //www.okayama-u.ac.jp/user/kouhou/ebulletin/
We love OKAYAMA UNIVERSITY: https://www.youtube.com/watch?v=7cXlttQIk3E
Okayama University Image Movie(2018)

Okayama University Medical Research Updates (OU-MRU)
The whole volume : OU-MRU (1- )
Vol.1:Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells from blood samples for genetic testing
Vol.2:Ensuring a cool recovery from cardiac arrest
Vol.3:Organ regeneration research leaps forward
Vol.4:Cardiac mechanosensitive integrator
Vol.5:Cell injections get to the heart of congenital defects
Vol.6:Fourth key molecule identified in bone development
Vol.7:Anticancer virus solution provides an alternative to surgery
Vol.8:Light-responsive dye stimulates sight in genetically blind patients
Vol.9:Diabetes drug helps towards immunity against cancer
Vol.10:Enzyme-inhibitors treat drug-resistant epilepsy
Vol.11:Compound-protein combination shows promise for arthritis treatment
Vol.12:Molecular features of the circadian clock system in fruit flies
Vol.13:Peptide directs artificial tissue growth
Vol.14:Simplified boron compound may treat brain tumours
Vol.15:Metamaterial absorbers for infrared inspection technologies
Vol.16:Epigenetics research traces how crickets restore lost limbs
Vol.17:Cell research shows pathway for suppressing hepatitis B virus
Vol.18:Therapeutic protein targets liver disease
Vol.19:Study links signalling protein to osteoarthritis
Vol.20:Lack of enzyme promotes fatty liver disease in thin patients
Vol.21:Combined gene transduction and light therapy targets gastric cancer
Vol.22:Medical supportive device for hemodialysis catheter puncture
Vol.23:Development of low cost oral inactivated vaccines for dysentery
Vol.24:Sticky molecules to tackle obesity and diabetes
Vol.25:Self-administered aroma foot massage may reduce symptoms of anxiety
Vol.26:Protein for preventing heart failure
Vol.27:Keeping cells in shape to fight sepsis
Vol.28:Viral-based therapy for bone cancer
Vol.29:Photoreactive compound allows protein synthesis control with light
Vol.30:Cancer stem cells’ role in tumor growth revealed
Vol.31:Prevention of RNA virus replication
Vol.32:Enzyme target for slowing bladder cancer invasion
Vol.33:Attacking tumors from the inside
Vol.34:Novel mouse model for studying pancreatic cancer
Vol.35:Potential cause of Lafora disease revealed
Vol.36:Overloading of protein localization triggers cellular defects
Vol.37:Protein dosage compensation mechanism unravelled
Vol.38:Bioengineered tooth restoration in a large mammal
Vol.39:Successful test of retinal prosthesis implanted in rats
Vol.40:Antibodies prolong seizure latency in epileptic mice
Vol.41:Inorganic biomaterials for soft-tissue adhesion
Vol.42:Potential drug for treating chronic pain with few side effects
Vol.43:Potential origin of cancer-associated cells revealed
Vol.44:Protection from plant extracts
Vol.45:Link between biological-clock disturbance and brain dysfunction uncovered
Vol.46:New method for suppressing lung cancer oncogene
Vol.47:Candidate genes for eye misalignment identified
Vol.48:Nanotechnology-based approach to cancer virotherapy
Vol.49:Cell membrane as material for bone formation
Vol.50:Iron removal as a potential cancer therapy
Vol.51:Potential of 3D nanoenvironments for experimental cancer
Vol.52:A protein found on the surface of cells plays an integral role in tumor growth and sustenance
Vol.53:Successful implantation and testing of retinal prosthesis in monkey eyes with retinal degeneration
Vol.54:Measuring ion concentration in solutions for clinical and environmental research
Vol.55:Diabetic kidney disease: new biomarkers improve the prediction of the renal prognosis
Vol.56:New device for assisting accurate hemodialysis catheter placement
Vol.57:Possible link between excess chewing muscle activity and dental disease
Vol.58:Insights into mechanisms governing the resistance to the anti-cancer medication cetuximab
Vol.59:Role of commensal flora in periodontal immune response investigated
Vol.60:Role of commensal microbiota in bone remodeling
Vol.61:Mechanical stress affects normal bone development
Vol.62:3D tissue model offers insights into treating pancreatic cancer
Vol.63:Promising biomarker for vascular disease relapse revealed
Vol.64:Inflammation in the brain enhances the side-effects of hypnotic medication
Vol.65:Game changer: How do bacteria play Tag ?
Vol.66:Is too much protein a bad thing?
Vol.67:Technology to rapidly detect cancer markers for cancer diagnosis
Vol.68:Improving the diagnosis of pancreatic cancer
Vol.69:Early gastric cancer endoscopic diagnosis system using artificial intelligence
Vol.70:Prosthetics for Retinal Stimulation
Vol.71:The nervous system can contribute to breast cancer progression
Vol.72:Synthetic compound provides fast screening for potential drugs
Vol.73:Primary intraocular lymphoma does not always spread to the central nervous system
Vol.74:Rising from the ashes—dead brain cells can be regenerated after traumatic injury
Vol.75:More than just daily supplements — herbal medicines can treat stomach disorders