Tropomodulin 1 directly controls thin filament length in both wild-type and tropomodulin 4-deficient skeletal muscle
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Tropomodulin 1 directly controls thin filament length in both wild-type and tropomodulin 4-deficient skeletal muscle. / Gokhin, David S; Ochala, Julien; Domenighetti, Andrea A; Fowler, Velia M.
I: Development (Cambridge, England), Bind 142, Nr. 24, 15.12.2015, s. 4351-62.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Tropomodulin 1 directly controls thin filament length in both wild-type and tropomodulin 4-deficient skeletal muscle
AU - Gokhin, David S
AU - Ochala, Julien
AU - Domenighetti, Andrea A
AU - Fowler, Velia M
N1 - © 2015. Published by The Company of Biologists Ltd.
PY - 2015/12/15
Y1 - 2015/12/15
N2 - The sarcomeric tropomodulin (Tmod) isoforms Tmod1 and Tmod4 cap thin filament pointed ends and functionally interact with the leiomodin (Lmod) isoforms Lmod2 and Lmod3 to control myofibril organization, thin filament lengths, and actomyosin crossbridge formation in skeletal muscle fibers. Here, we show that Tmod4 is more abundant than Tmod1 at both the transcript and protein level in a variety of muscle types, but the relative abundances of sarcomeric Tmods are muscle specific. We then generate Tmod4(-/-) mice, which exhibit normal thin filament lengths, myofibril organization, and skeletal muscle contractile function owing to compensatory upregulation of Tmod1, together with an Lmod isoform switch wherein Lmod3 is downregulated and Lmod2 is upregulated. However, RNAi depletion of Tmod1 from either wild-type or Tmod4(-/-) muscle fibers leads to thin filament elongation by ∼15%. Thus, Tmod1 per se, rather than total sarcomeric Tmod levels, controls thin filament lengths in mouse skeletal muscle, whereas Tmod4 appears to be dispensable for thin filament length regulation. These findings identify Tmod1 as the key direct regulator of thin filament length in skeletal muscle, in both adult muscle homeostasis and in developmentally compensated contexts.
AB - The sarcomeric tropomodulin (Tmod) isoforms Tmod1 and Tmod4 cap thin filament pointed ends and functionally interact with the leiomodin (Lmod) isoforms Lmod2 and Lmod3 to control myofibril organization, thin filament lengths, and actomyosin crossbridge formation in skeletal muscle fibers. Here, we show that Tmod4 is more abundant than Tmod1 at both the transcript and protein level in a variety of muscle types, but the relative abundances of sarcomeric Tmods are muscle specific. We then generate Tmod4(-/-) mice, which exhibit normal thin filament lengths, myofibril organization, and skeletal muscle contractile function owing to compensatory upregulation of Tmod1, together with an Lmod isoform switch wherein Lmod3 is downregulated and Lmod2 is upregulated. However, RNAi depletion of Tmod1 from either wild-type or Tmod4(-/-) muscle fibers leads to thin filament elongation by ∼15%. Thus, Tmod1 per se, rather than total sarcomeric Tmod levels, controls thin filament lengths in mouse skeletal muscle, whereas Tmod4 appears to be dispensable for thin filament length regulation. These findings identify Tmod1 as the key direct regulator of thin filament length in skeletal muscle, in both adult muscle homeostasis and in developmentally compensated contexts.
KW - Actin Cytoskeleton/metabolism
KW - Animals
KW - Down-Regulation/genetics
KW - Female
KW - Gene Deletion
KW - Gene Knockdown Techniques
KW - Mice, Inbred C57BL
KW - Microfilament Proteins/metabolism
KW - Muscle Proteins/metabolism
KW - Muscle, Skeletal/metabolism
KW - Phenotype
KW - Protein Isoforms/metabolism
KW - RNA Interference
KW - Sarcomeres/metabolism
KW - Tropomodulin/deficiency
KW - Up-Regulation/genetics
U2 - 10.1242/dev.129171
DO - 10.1242/dev.129171
M3 - Journal article
C2 - 26586224
VL - 142
SP - 4351
EP - 4362
JO - Development
JF - Development
SN - 0950-1991
IS - 24
ER -
ID: 240788487