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J Med Genet. 2013 Jun;50(6):383-92. doi: 10.1136/jmedgenet-2012-101470. Epub 2013 Apr 9.

Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations.

Author information

1
Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

Abstract

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.

KEYWORDS:

Muscle disease

PMID:
23572184
PMCID:
PMC3865762
DOI:
10.1136/jmedgenet-2012-101470
[Indexed for MEDLINE]
Free PMC Article
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