Lecture 3: Muscular Dystrophies I PDF

Lecture 3 Muscular Dystrophies I Dr. Kinga Vojnits PDHC CREATE Program Coordinator Research Associate, Pakpour Laboratory | Biomedical Microbiome Research School of Engineering The University of British Columbia | Okanagan Campus...

Lecture 3 Muscular Dystrophies I Dr. Kinga Vojnits PDHC CREATE Program Coordinator Research Associate, Pakpour Laboratory | Biomedical Microbiome Research School of Engineering The University of British Columbia | Okanagan Campus © Vojnits. Not to be copied, used, revised, or distributed without explicit written permission from the copyright owner.  End term group project 2 GROUPS 1. Elena Sta Maria, Sathvika Kalidindi, Isabelle Tran, Ethan Price 2. Dylan Klatt, Liam Zandvliet, Loreena Semple, Shaena Gyorfi 3. Marina Giannotti, Quinn Anderson, Sarah Pulfer, Carla Girbes Sendin 4. Amber Rashid, Baljot Mann, Tanya Makhija, Zaya Enkhtur 5. Ali Amiri, Joanne Lee, Helena Cho, David Yuan 6. Ava Nguyen, Kara Stayberg, Mya Hurst, Arantxa Da Fonseca 7. Tinu Tope-Awofeko, Mahan Sahu, Jasmin Mun Langdon, Jonah Dizon 8. Hephzibah Bomide, Cecilia Lu, Shane Andal, Sean Chambers 9. Karen Sticchi Zambom, Paige Pomeroy, Kadence Balderston, Natasha Jones. 10. Vincent Malinis, James Chiu, Jamie Rahn, Madelaine Wong 11. Deni Corrigan, Abby Bartoshewski, Maytham Abdul, Natasha Jones 12. Jenna Marinus, Brooklyn Becker, Benjamin Bigiremana, Hudson Young, Matthew Stewart 13. Reece Alexander, Lynn Anne Kabasiita, Melissa Muganga 14. Manjot Gill, Rory Garcia, Arlene Bassi 15. Sophie Bennett, Maya Chima-Nnadozie, Jacob Koole, Randy Ufimzeff BIOC 407  End term group project 3 Theme: Research Proposal Throughout the course, students form groups working on a term project focused on selected diseases. Research topics will be chosen by the student groups to explore current knowledge and understanding of the biochemical basis of the selected disease. Any disease that we have not covered in detail during the class lectures or assignments can be chosen from these groups of diseases: genetic diseases, protein misfolding diseases, metabolic diseases, or hematological diseases. The goal is to develop an initial theoretical concept for enhancing our understanding of the biochemical basis of select diseases. Proposals should focus on identifying research gaps and propose research ideas, and experiments that help identify mechanisms that are involved in the select disease. Due Written proposal submission: 31st March 2025 Group Presentations: April 1st – April 8th 2025 BIOC 407  Recap from previous lecture 4 Congenital disorders or diseases are those present at birth, although most are present prior to birth even if they are not apparent then They can be classified in many different ways: Congenital physical anomalies Congenital malformations Genetic disorders Spina bifida Cleft lip/cleft palate Cystic fibrosis Huntington’s disease BIOC 407 5 Deletions/translocations BIOC 407  Deletions/translocations 6 For example, DiGeorge syndrome (1:4,000 prevalence): Depending on the location of the deletion, symptoms vary even within one family Deletion occurs near the middle of the chromosome 22 at a location designated 22q11.2 (long arm, region 1, band 1, sub- band 2) Can affect diverse parts of the body congenital heart disease defects in the palate immune system defects learning disabilities kidney defects hearing loss BIOC 407 7 Cri du chat or cat cry syndrome was first described in a group of patients with a mew-like cry, and abnormalities: Low birth weight, Failure to thrive, Cri du chat Hypotonia, Psychomotor retardation, Microcephaly, syndrome Round face and anti-mongoloid slant to the eyes. Most children, but not all, have low weight for age, and to a lesser extent, shortened height for age. The cri-du-chat syndrome is one of the most common human deletion syndromes, with an incidence of 1 in 20,000 to 1 in 50,000 births. Approximately 85 percent of cases result from a de novo partial deletion of the short arm of chromosome 5 (the deleted chromosome is of paternal origin in 80 %); the remaining cases derive from a parental translocation involving 5p. BIOC 407 8 Cri du chat syndrome BIOC 407  X linked recessive 9 Hemophilia A coagulation factor VIII Duchenne muscular dystrophy lack of dystrophin Becker’s muscular dystrophy abnormal dystrophin BIOC 407  Goals of today’s lecture 10 What are muscular dystrophies? Duchenne Muscular Dystrophy (DMD) Mode of Inflammation inheritance Pathophysiology: Calcium overload Becker Muscular Fiber type Dystrophy (BMD) differences BIOC 407  Muscular dystrophies 11 A group of diseases characterized by progressive degeneration of both skeletal and cardiac muscle Causes Inheritance Dominant genes Recessive gene Depends on the age when symptoms appear, and the types of symptoms that develop. Risk Because these are inherited disorders, risk include a family history of muscular dystrophy How many people are affected? It is estimated that between 50,000 – 250,000 are affected annually. 1 per 3500 live male births BIOC 407  Muscular dystrophies 12 BIOC 407  Muscular dystrophies 13 Muscular dystrophy is a heterogenous group of inherited disorders recognized by progressive degenerative muscle weakness and loss of muscle tissue (started in childhood). Affect muscles strength and action. Generalized or localized. Skeletal muscle and other organs may be involved Limitations: Difficulties with walking or Maintaining posture, Muscle spasms. Neurological, Behavioral, Cardiac, or other Functional limitations. BIOC 407 14 Muscular dystrophies BIOC 407  Skeletal muscle 15 Pannerec et al, 2012 TRENDS in Molecular Medicine Muscle stem cells Mesenchymal progenitors Pericytes Connective tissue cells Normal muscle Dystrophic muscle https://www.nature.com/articles/nrm2024#Fig1 BIOC 407  Different types 16 BIOC 407 17 DMD (Duchenne Muscular Dystrophy) ENGR 598 18 DMD (Duchenne) The FEBS Journal, Volume: 287, Issue: 18, Pages: 3879-3887, First published: 01 July 2020, DOI: (10.1111/febs.15466)  DMD (Duchenne) 20 Severe and debilitating disease Primarily affects boys (X-linked transmittance) 1 in every 10,500 Canadian boys 1 in 3,500 boys worldwide Skeletal muscle weakness There appears to be mild cognitive impairment as well No cure Cardiomyopathy is a cause of death BIOC 407  Lifespan with DMD 21 BIOC 407 22 Is caused by the complete absence of dystrophin, which can be due to either large deletions of the gene or to point mutations DMD causes that cause insertion of a stop codon [exon 45 most commonly involved] BIOC 407  The genetic cause of DMD 23 BIOC 407  The dystrophin gene 24 BIOC 407  Functional domains of dystrophin 25 BIOC 407  Types of DMD mutations 26 BIOC 407  The genetic cause of DMD 27 https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1360224/full TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/) BIOC 407  Mode of inheritance: X-linked recessive 28 Mutation on the X chromosome to the dystrophin gene. Recessive means that in females where there are two X chromosomes; both have to be mutated in order for the disease to present itself. If the female only has one mutated X chromosome, then she is otherwise healthy but is a carrier mother. Males only have one X chromosome, and so if they receive the mutated X-chromosome from the mother carrier then they will have the disease. Carrier mothers have a 50% chance of passing on the mutated dystrophin gene to their sons. For DMD boys: 70% of cases are inherited from their mothers, other 30% are sporadic (spontaneous mutation). BIOC 407  Dystrophin https://www.frontiersin.org/files/Articles/859930/fmed-09-859930-HTML/image_m/fmed-09-859930-g001.jpg 29  Dystrophin stabilizes muscle membranes 30 BIOC 407  Dystrophin: a muscular shock absorber 31 BIOC 407 Loss of dystrophin causes DMD 32  Muscle degeneration 33 Absence of dystrophin leads to muscle fragility and extensive muscle degeneration Serum creatine kinase is a marker of muscle damage Healthy muscle fiber Damaged muscle fiber with DMD BIOC 407  Inflammation – healthy regeneration 34 Injury leads to orchestrated muscle repair. Activation of satellite cells that proliferate and differentiate and fuse to damaged muscles. Inflammation plays an important role in the early stages – helping to clear the debris. In the later stages of repair, inflammation must be reduced to allow for differentiation and fusion. BIOC 407  Inflammation 35 – healthy regeneration This orchestrated inflammatory response must be acute! What do you think happens if inflammation persists? Secondary necrosis https://www.sciencedirect.com/science/article/pii/S2214031X17300621 BIOC 407  Inflammation – DMD 36 The absence of dystrophin causes constant degeneration and thus chronic inflammation BIOC 407  Calcium and muscle https://journals.physiology.org/doi/full/10.1152/ajpcell.00056.2015 37  Calcium influx 38 Calcium levels outside of a muscle fiber is ~ 2 mM Calcium levels inside the muscle at rest is 100 nM. In the sarcoplasmic reticulum it is about 1 mM In DMD, damage to the muscle plasma membrane (because of the absence of dystophin) causes an influx of calcium into the muscle fiber. Too much calcium in the muscle fiber is bad! Reactive oxygen species (ROS) production Calpain activation BIOC 407  Reactive oxygen species (ROS) 39 ROS damage can lead to a domino effect = oxidative stress BIOC 407 https://www.mdpi.com/2073-4409/13/7/574  Muscle physiology – fiber types 40 https://www.intechopen.com/chapters/62465 BIOC 407  Another key difference between fiber types 41 For DMD specifically: the fast glycolic fibers are MORE susceptible to the dystrophic pathology. This is due to a number of reasons including: More force produced – stronger contractions lead to more stress Less PGC-1a – the master regulator of mitochondrial biogenesis Less utrophin BIOC 407  Peroxisome proliferator-activated receptor gamma 42 coactivator 1a Transcription factor PGC-1 alpha Master regulator of mitochondrial biogenesis Activated by exercise and can promote the slow oxidative phenotype BIOC 407  Dystrophin and utrophin – do they look the same? 43 Utrophin: structural and functional paralogue of dystrophin, ubiquitously expressed throughout the sarcolemma in foetal muscle. Dystrophin Utrophin is progressively replaced by dystrophin during late embryonic stages, restricted to the myotendinous and neuromuscular junctions and blood vessels in normal adult muscle. Utrophin It was proposed that utrophin could act as a surrogate to compensate for the lack of dystrophin in DMD Advances in genetic therapeutic strategies for Duchenne muscular dystrophy BIOC 407 44 BMD (Becker Muscular Dystrophy) BIOC 407 45 BMD (Becker) BIOC 407  Clinical features 46 Less common 1: 30,000 live male births Less severe Family history: atypical MD Similar and less severe than DMD Onset: age > 7 BIOC 407  BMD (Becker) 47 Patients are found to have a truncated dystrophin protein due to in-frame skipping of exons which results in loss of the central portion of the molecule (shortening of the ‘rod domain’ by 50% is possible) The resulting protein still retains some function The onset of symptoms is later and the progression of the disease is slower Sometimes the first sign of the disease is a cardiac abnormality BIOC 407 48 BMD (Becker) BIOC 407  Paper to read/study for next lecture 49 Review this paper in detail: https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2023.1261318/full BIOC 407  Literature 50 Duchenne muscular dystrophy: Dongsheng Duan et al: https://www.nature.com/articles/s41572-021-00248-3 Biochemical and molecular basis of muscle disease: Susan C. Brown and Cecilia Jimenez-Mallebera Skeletal Muscle Fiber Types in Neuromuscular Diseases: Jennifer Glaser and Masatoshi Suzuki: https://www.intechopen.com/chapters/62465 Mitochondria and Reactive Oxygen Species:The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy: Silvia Rosanna Casat https://www.mdpi.com/2073-4409/13/7/574 The discovery of dystrophin, the protein product of the Duchenne muscular dystrophy gene: Eric P. Hoffman. The FEBS Journal,Volume: 287, Issue: 18, Pages: 3879-3887, First published: 01 July 2020, DOI: (10.1111/febs.15466) https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30024-3/fulltext CASE REPORT article, Front. Pediatr., 19 November 2023, Sec. Genetics of Common and Rare Diseases, Volume 11 - 2023 | https://doi.org/10.3389/fped.2023.1261318 https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2023.1261318/full BIOC 407