Sarcomere Biology
Definition
The cardiac sarcomere is the basic contractile unit of the cardiomyocyte, comprising interdigitated thick (myosin) and thin (actin) filaments organised in the A-band and I-band. Sarcomeric proteins — MYH7 (β-myosin heavy chain), MYBPC3 (cardiac myosin-binding protein C), TNNT2 (troponin T), TNNI3 (troponin I), TPM1 (tropomyosin), and titin (TTN) — regulate crossbridge cycling, Ca²⁺ sensitivity, and force generation. Mutations in sarcomere genes account for the majority of familial hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy.
Key Concepts
Sarcomere Architecture
- Thick filaments (myosin): MYH7 (and MYH6 in atria) plus accessory proteins; located in the A-band. MYH7 is the second most frequently mutated HCM gene (~25–40% of HCM) after MYBPC3. (sources/mybpc3-gene-2015 — medium)
- Thin filaments (actin + regulatory proteins): G-actin polymerises into F-actin strands; the troponin complex (troponin C/I/T) and tropomyosin control Ca²⁺-dependent thin filament activation. Troponin C binds Ca²⁺; troponin I inhibits actomyosin ATPase at diastolic Ca²⁺; tropomyosin shifts to expose myosin-binding sites during systole.
- C-zone (cross-bridge-bearing region): cMyBP-C (MYBPC3 product) forms transverse stripes at ~43 nm intervals — 7–9 stripes per half thick filament — in this zone. (sources/mybpc3-gene-2015)
- Titin: Giant elastic protein spanning Z-disc to M-band; molecular spring controlling passive diastolic stiffness. TTN truncating variants are the most common cause of genetic DCM (~25%). (sources/mybpc3-gene-2015)
Crossbridge Cycling and cMyBP-C Regulation
- Crossbridge cycle: During systole, Ca²⁺ binds troponin C → tropomyosin shifts → myosin S1 heads bind actin → ADP release (force-generating step) → ATP binding → crossbridge detachment → ATP hydrolysis resets myosin.
- cMyBP-C as a crossbridge brake: The N-terminal C1-M-C2 region of cMyBP-C binds myosin S2 heads — constraining them and limiting loaded shortening velocity and power output during diastole. Loss of cMyBP-C (knockout mice) accelerates crossbridge cycling and increases force redevelopment. (sources/mybpc3-gene-2015 — medium)
- Dual filament coordination: cMyBP-C N-terminus stabilises the ON state of thin filaments and the OFF state of thick filaments — coordinating both filament systems to fine-tune Ca²⁺ activation relationship. (sources/mybpc3-gene-2015)
- Phosphorylation switch: PKA-mediated phosphorylation at M-motif sites (Ser273/282/302) shifts cMyBP-C from myosin S2 to actin binding → accelerates crossbridge cycling, enhances force development, and promotes diastolic relaxation during beta-adrenergic stimulation. This is the molecular basis of the inotropic/lusitropic response. (sources/mybpc3-gene-2015)
Myofilament Ca²⁺ Sensitivity — The HCM Final Common Pathway
- Increased myofilament Ca²⁺ sensitivity is the central functional consequence of most HCM mutations — including MYBPC3 haploinsufficiency (less crossbridge braking), MYH7 gain-of-function, TNNT2, and TPM1 mutations. The increased sensitivity means more crossbridges remain active at diastolic Ca²⁺ concentrations → impaired relaxation. (sources/mybpc3-gene-2015 — medium)
- HCM therapeutic target: Mavacamten and aficamten (allosteric myosin inhibitors) reduce crossbridge cycling by stabilising myosin in its folded-back OFF state — directly targeting excessive myofilament activation. (sources/mybpc3-gene-2015)
Sarcomere Mutations and Disease
- HCM: MYBPC3 (40–50%) + MYH7 (25–40%) account for ~70–80% of genotype-positive HCM. Mutations cause hypercontractility, diastolic dysfunction, and secondary compensatory hypertrophy. (sources/mybpc3-gene-2015)
- DCM: Sarcomere mutations cause DCM via loss-of-function mechanisms reducing force generation (MYH7 hypocontractile variants, MYBPC3 mutations reducing effective crossbridge number). TTN truncating variants dominate genetic DCM. (sources/mybpc3-gene-2015)
- Restrictive CMP: Troponin mutations (TNNT2, TNNI3) causing extreme myofilament Ca²⁺ sensitivity produce severe diastolic restriction.
Contradictions / Open Questions
- Mechanism of increased Ca²⁺ sensitivity — not uniform: Whether increased Ca²⁺ sensitivity arises primarily from reduced crossbridge braking (MYBPC3 haploinsufficiency), altered tropomyosin positioning, or secondary Ca²⁺ handling changes (RyR2 interaction) remains incompletely resolved for individual gene mutations. (sources/mybpc3-gene-2015)
- cMyBP-C mouse models vs human: Reduced K⁺ currents in Mybpc3 knock-in mice are proposed as a proarrhythmic mechanism in HCM — but were not replicated in human MYBPC3-homozygous engineered heart tissue or surgical myectomy samples. Species translational gap undermines mouse-model-guided antiarrhythmic drug development for human HCM. (sources/mybpc3-gene-2015)
Connections
- Related to entities/MYBPC3
- Related to entities/HCM
- Related to entities/DCM
- Related to concepts/Haploinsufficiency
- Related to concepts/AAV-Gene-Delivery
- Related to concepts/Ion-Channel-Remodeling-in-HCM