Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms.
In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters. Interestingly, we identified two divergent, mutation-specific pathophysiological mechanisms. (i) The TPM2-null and TPM3-R167H mutations both decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production. The TPM3-R167H mutation also induced a concomitant reduction in thin filament length. (ii) In contrast, the TPM2-E181K mutation increased thin filament activation, cross-bridge binding and force generation. In the former mechanism, modulating thin filament activation by administering troponin activators (CK-1909178 and EMD 57033) to single membrane-permeabilized fibers carrying tropomyosin mutations rescued the thin filament activation defect associated with the pathophysiology. Therefore, administration of troponin activators may constitute a promising therapeutic approach in the future.
Department of Neuroscience, Uppsala University, Uppsala, Sweden. julien.ochala@neuro.uu.se
Julien
J
Ochala
David S
DS
Gokhin
Isabelle
I
Pénisson-Besnier
Susana
S
Quijano-Roy
Nicole
N
Monnier
Joël
J
Lunardi
Norma B
NB
Romero
Velia M
VM
Fowler
D008841:Actin Cytoskeleton; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000151:congenital*; D009154:Mutation; D011804:Quinolines / Q000494:pharmacology; D013829:Thiadiazines / Q000494:pharmacology; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism
D011804:Quinolines; C518659:TPM2 protein, human; C498783:TPM3 protein, human; D013829:Thiadiazines; D014335:Tropomyosin; C070609:EMD 53998