Cytoskeletal Diseases 2 Flashcards
Striated muscle
Striated pattern is a consequence of intermediate filaments which link all the Z-lines of neighbouring myofibrils
- found in cardiac and skeletal muscle
The cardiomyocytes are tightly connected by intercalated discs (disorganisation of myocyte arrangement reduces efficiency of contraction)
Myosin structure
Hexameric structure made of 6 subunits:
- 2x heavy chains dimerize via coiled-coil formation (in LMM and S-2)
- LMM associates to form filaments (tails assemble into thick filament)
- S1 = globular region where each of the heavy chains bind 1 essential and 1 regulatory light chain (4 in total)
How myosin drives muscle contraction
2 heads on long thin tail (155 x 2nm) each ~16nm long
- hydrolyse ATP and bind actin, forming ‘crossbridges’
Myosin level changes orientation during power stroke
- actin binding cleft closes when myosin is strongly bound to actin
Mysoin arranged into sarcomeres
Regulation of sarcomere activation
- Ca2+ binding to troponin allows myosin to bind
- Myosin Binding Protein - C (MYBP-C) can tether myosin heads to thick filament backbone
- switched on when actin-myosin regulatory light chain is phosphorylated (otherwise MYBP-C keeps it off)
Hypertrophic CardioMyopathy (HCM)
An intrinsic myocardial disorder characterised by unexplained Left Ventricular Hypertrophy (LVH) that occurs in the absence of pressure overload or storage/infiltrative disease
- 1/500 people carry a mutant gene causing HCM
- main cause of sudden cardiac death in young people (death from arrythmia - fibrillation/tachycardia)
Effects of HCM on heart
Ventricular Septum (VS) bulges into left ventricular outflow tract
- disordered cellular architecture with adjacent hypertrophied cardiac muscle cells
- coronary artery with narrow lumen (due to adjacent enlarged hypertrophic cells)
- Fibrotic scar following myocyte death
HCM symptoms
shortness of breath, chest pain, palpitations, orthostasis (head rush), presyncope (light headedness) and syncope (fainting)
Death: biggest non-violent killed of U20s and big problem in athletes (e.g. Fabrice Muamba)
Cause of HCM
Caused by mutations in muscle sarcomere proteins:
- Most severe = MYH7: beta-cardiac myosin heavy chain (15-45%)
- R403Q mutation = 1st HCM mutation found (basic charged arginine residue changed to neutral glutamine residue causing change in charge)
»> 3x reduced output per ATP
»> less time strongly attached to actin = lower force and therefore compensatory hypertrophy
Around 400 different mutations (mostly missense) associated with HCM
- 60% in S1 motor domain, 20% in S2 and 20% in LMM
Mutated proteins in HCM
MyBPC: C-protein mostly mild effects later in life
- cardiac isoform = cMyBP-C (1 per 9 myosin molecules)
- Key modulator of force output
PKA phosphorylation of MyBPC
Protein Kinase A’s phosphorylation of MyBPC allows myosin to interact with actin
- when dephosphorylated, C1-M-C2 domains are tightly bound to Myosin-S2
- Upon phosphorylation, M domain releases its interaction with Myosin-S2 & Actin
- When mutated, protein is truncated leading to haploinsufficiency
Haploinsufficiency
When the normal allele can’t make enough protein to compensate for the mutant allele
- the truncated MyBPC is quickly degraded: nonsense-mediated mRNA decay (NMD) & Ubiquitin-proteosome system (UPS)
- reduced C-protein levels = increased Ca2+ sensitivity (the MyBPC is less able to modify force output in cardiomyocytes)
Treating HCM
Beta-blockers and Ca channel blockers
- slow heart rate & increase diastolic filling time
Anti-arrythmias and/or implantable cardioverter-defibrillator
- maintain sinus rhythm
Ethanol Septal ablation (surgery)
- removing obstruction of ventricular outflow
Mutation in myosin tail (S2/LMM)
Cause HCM, DCM & Skeletal muscle disease
- S2 & LMM = coiled-coils of repeating heptad motif with a hydrophobic seam
If mutant, myosin can’t assemble into thick filaments due to altered amino acid sequence with proline incorporated:
- proline introduce a bing kink into alpha helix, disrupting coiled-coil
- Deletion of amino acid shifts the hydrophobic seam
