Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations. J Med Genet 2013 Jun;50(6):383-92
Date
04/11/2013Pubmed ID
23572184Pubmed Central ID
PMC3865762DOI
10.1136/jmedgenet-2012-101470Scopus ID
2-s2.0-84878843972 (requires institutional sign-in at Scopus site) 42 CitationsAbstract
BACKGROUND: Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebulin, which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK-2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations.
METHODS: Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 μM CK-2066260 on force production was assessed.
RESULTS: Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calcium-sensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation-without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle.
CONCLUSIONS: Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.
Author List
de Winter JM, Buck D, Hidalgo C, Jasper JR, Malik FI, Clarke NF, Stienen GJ, Lawlor MW, Beggs AH, Ottenheijm CA, Granzier HAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultBiopsy
Calcium
Child, Preschool
Humans
Imidazoles
Infant
Muscle Fibers, Skeletal
Muscle Proteins
Muscle Strength
Mutation
Myopathies, Nemaline
Pyrazines
Treatment Outcome
Troponin
Young Adult