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The fraction of str...
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Lindqvist, JohanUppsala universitet,Klinisk neurofysiologi
(author)
The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4(L342Q)
- Article/chapterEnglish2013
Publisher, publication year, extent ...
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2013-01-01
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The Company of Biologists,2013
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-202382
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-202382URI
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https://doi.org/10.1242/dmm.011155DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Myosinopathies have emerged as a new group of diseases and are caused by mutations in genes encoding myosin heavy chain (MyHC) isoforms. One major hallmark of these diseases is skeletal muscle weakness or paralysis, but the underlying molecular mechanisms remain unclear. Here, we have undertaken a detailed functional study of muscle fibers from Myh4(arl) mice, which carry a mutation that provokes an L342Q change within the catalytic domain of the type IIb skeletal muscle myosin protein MYH4. Because homozygous animals develop rapid muscle-structure disruption and lower-limb paralysis, they must be killed by postnatal day 13, so all experiments were performed using skeletal muscles from adult heterozygous animals (Myh4(arl)/+). Myh4(arl)/+ mice contain MYH4(L342Q) expressed at 7% of the levels of the wild-type (WT) protein, and are overtly and histologically normal. However, mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized fibers revealed, upon maximal Ca2+ activation, higher stiffness as well as altered meridional and equatorial reflections in Myh4(arl)/+ mice when compared with age-matched WT animals. Under rigor conditions, by contrast, no difference was observed between Myh4(arl)/+ and WT mice. Altogether, these findings prove that, in adult MYH4(L342Q) heterozygous mice, the transition from weak to strong myosin cross-bridge binding is facilitated, increasing the number of strongly attached myosin heads, thus enhancing force production. These changes are predictably exacerbated in the type IIb fibers of homozygous mice, in which the embryonic myosin isoform is fully replaced by MYH4(L342Q), leading to a hypercontraction, muscle-structure disruption and lower-limb paralysis. Overall, these findings provide important insights into the molecular pathogenesis of skeletal myosinopathies.
Added entries (persons, corporate bodies, meetings, titles ...)
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Iwamoto, Hiroyuki
(author)
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Blanco, Gonzalo
(author)
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Ochala, JulienUppsala universitet,Klinisk neurofysiologi(Swepub:uu)juloc433
(author)
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Uppsala universitetKlinisk neurofysiologi
(creator_code:org_t)
Related titles
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In:Disease Models and Mechanisms: The Company of Biologists6:3, s. 834-8401754-84031754-8411
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