Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice

Kristen A. Baltgalvis; Michele A. Jaeger; Daniel P. Fitzsimons; Stanley A. Thayer; Dawn A. Lowe; James M. Ervasti

doi:10.1186/2044-5040-1-32

Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice

Kristen A. Baltgalvis, Michele A. Jaeger, Daniel P. Fitzsimons, Stanley A. Thayer, Dawn A. Lowe, James M. Ervasti

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Abstract

Background: γ-cytoplasmic (γ-_cyto) actin levels are elevated in dystrophin-deficient mdx mouse skeletal muscle. The purpose of this study was to determine whether further elevation of γ-_cytoactin levels improve or exacerbate the dystrophic phenotype of mdx mice.Methods: We transgenically overexpressed γ-_cytoactin, specifically in skeletal muscle of mdx mice (mdx-TG), and compared skeletal muscle pathology and force-generating capacity between mdx and mdx-TG mice at different ages. We investigated the mechanism by which γ-_cytoactin provides protection from force loss by studying the role of calcium channels and stretch-activated channels in isolated skeletal muscles and muscle fibers. Analysis of variance or independent t-tests were used to detect statistical differences between groups.Results: Levels of γ-_cytoactin in mdx-TG skeletal muscle were elevated 200-fold compared to mdx skeletal muscle and incorporated into thin filaments. Overexpression of γ-_cytoactin had little effect on most parameters of mdx muscle pathology. However, γ-_cytoactin provided statistically significant protection against force loss during eccentric contractions. Store-operated calcium entry across the sarcolemma did not differ between mdx fibers compared to wild-type fibers. Additionally, the omission of extracellular calcium or the addition of streptomycin to block stretch-activated channels did not improve the force-generating capacity of isolated extensor digitorum longus muscles from mdx mice during eccentric contractions.Conclusions: The data presented in this study indicate that upregulation of γ-_cytoactin in dystrophic skeletal muscle can attenuate force loss during eccentric contractions and that the mechanism is independent of activation of stretch-activated channels and the accumulation of extracellular calcium.

Original language	English (US)
Article number	32
Journal	Skeletal muscle
Volume	1
Issue number	1
DOIs	https://doi.org/10.1186/2044-5040-1-32
State	Published - Oct 13 2011

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Training Program in Muscle Research grant AR007612, grants from the National Institutes of Health AR049899 (to JME), DA07304 (to SAT) and AG036827 (to DAL) and a grant from the National Science Foundation IOS0814549 (to SAT).

Keywords

Calcium
Costamere
Dystrophin
Skeletal muscle injury
Stretch-activated channels

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title = "Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice",

abstract = "Background: γ-cytoplasmic (γ-cyto) actin levels are elevated in dystrophin-deficient mdx mouse skeletal muscle. The purpose of this study was to determine whether further elevation of γ-cyto actin levels improve or exacerbate the dystrophic phenotype of mdx mice.Methods: We transgenically overexpressed γ-cyto actin, specifically in skeletal muscle of mdx mice (mdx-TG), and compared skeletal muscle pathology and force-generating capacity between mdx and mdx-TG mice at different ages. We investigated the mechanism by which γ-cyto actin provides protection from force loss by studying the role of calcium channels and stretch-activated channels in isolated skeletal muscles and muscle fibers. Analysis of variance or independent t-tests were used to detect statistical differences between groups.Results: Levels of γ-cyto actin in mdx-TG skeletal muscle were elevated 200-fold compared to mdx skeletal muscle and incorporated into thin filaments. Overexpression of γ-cyto actin had little effect on most parameters of mdx muscle pathology. However, γ-cyto actin provided statistically significant protection against force loss during eccentric contractions. Store-operated calcium entry across the sarcolemma did not differ between mdx fibers compared to wild-type fibers. Additionally, the omission of extracellular calcium or the addition of streptomycin to block stretch-activated channels did not improve the force-generating capacity of isolated extensor digitorum longus muscles from mdx mice during eccentric contractions.Conclusions: The data presented in this study indicate that upregulation of γ-cyto actin in dystrophic skeletal muscle can attenuate force loss during eccentric contractions and that the mechanism is independent of activation of stretch-activated channels and the accumulation of extracellular calcium.",

keywords = "Calcium, Costamere, Dystrophin, Skeletal muscle injury, Stretch-activated channels",

author = "Baltgalvis, {Kristen A.} and Jaeger, {Michele A.} and Fitzsimons, {Daniel P.} and Thayer, {Stanley A.} and Lowe, {Dawn A.} and Ervasti, {James M.}",

note = "Funding Information: This work was supported by National Institutes of Health Training Program in Muscle Research grant AR007612, grants from the National Institutes of Health AR049899 (to JME), DA07304 (to SAT) and AG036827 (to DAL) and a grant from the National Science Foundation IOS0814549 (to SAT).",

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doi = "10.1186/2044-5040-1-32",

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T1 - Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice

AU - Baltgalvis, Kristen A.

AU - Jaeger, Michele A.

AU - Fitzsimons, Daniel P.

AU - Thayer, Stanley A.

AU - Lowe, Dawn A.

AU - Ervasti, James M.

N1 - Funding Information: This work was supported by National Institutes of Health Training Program in Muscle Research grant AR007612, grants from the National Institutes of Health AR049899 (to JME), DA07304 (to SAT) and AG036827 (to DAL) and a grant from the National Science Foundation IOS0814549 (to SAT).

PY - 2011/10/13

Y1 - 2011/10/13

N2 - Background: γ-cytoplasmic (γ-cyto) actin levels are elevated in dystrophin-deficient mdx mouse skeletal muscle. The purpose of this study was to determine whether further elevation of γ-cyto actin levels improve or exacerbate the dystrophic phenotype of mdx mice.Methods: We transgenically overexpressed γ-cyto actin, specifically in skeletal muscle of mdx mice (mdx-TG), and compared skeletal muscle pathology and force-generating capacity between mdx and mdx-TG mice at different ages. We investigated the mechanism by which γ-cyto actin provides protection from force loss by studying the role of calcium channels and stretch-activated channels in isolated skeletal muscles and muscle fibers. Analysis of variance or independent t-tests were used to detect statistical differences between groups.Results: Levels of γ-cyto actin in mdx-TG skeletal muscle were elevated 200-fold compared to mdx skeletal muscle and incorporated into thin filaments. Overexpression of γ-cyto actin had little effect on most parameters of mdx muscle pathology. However, γ-cyto actin provided statistically significant protection against force loss during eccentric contractions. Store-operated calcium entry across the sarcolemma did not differ between mdx fibers compared to wild-type fibers. Additionally, the omission of extracellular calcium or the addition of streptomycin to block stretch-activated channels did not improve the force-generating capacity of isolated extensor digitorum longus muscles from mdx mice during eccentric contractions.Conclusions: The data presented in this study indicate that upregulation of γ-cyto actin in dystrophic skeletal muscle can attenuate force loss during eccentric contractions and that the mechanism is independent of activation of stretch-activated channels and the accumulation of extracellular calcium.

AB - Background: γ-cytoplasmic (γ-cyto) actin levels are elevated in dystrophin-deficient mdx mouse skeletal muscle. The purpose of this study was to determine whether further elevation of γ-cyto actin levels improve or exacerbate the dystrophic phenotype of mdx mice.Methods: We transgenically overexpressed γ-cyto actin, specifically in skeletal muscle of mdx mice (mdx-TG), and compared skeletal muscle pathology and force-generating capacity between mdx and mdx-TG mice at different ages. We investigated the mechanism by which γ-cyto actin provides protection from force loss by studying the role of calcium channels and stretch-activated channels in isolated skeletal muscles and muscle fibers. Analysis of variance or independent t-tests were used to detect statistical differences between groups.Results: Levels of γ-cyto actin in mdx-TG skeletal muscle were elevated 200-fold compared to mdx skeletal muscle and incorporated into thin filaments. Overexpression of γ-cyto actin had little effect on most parameters of mdx muscle pathology. However, γ-cyto actin provided statistically significant protection against force loss during eccentric contractions. Store-operated calcium entry across the sarcolemma did not differ between mdx fibers compared to wild-type fibers. Additionally, the omission of extracellular calcium or the addition of streptomycin to block stretch-activated channels did not improve the force-generating capacity of isolated extensor digitorum longus muscles from mdx mice during eccentric contractions.Conclusions: The data presented in this study indicate that upregulation of γ-cyto actin in dystrophic skeletal muscle can attenuate force loss during eccentric contractions and that the mechanism is independent of activation of stretch-activated channels and the accumulation of extracellular calcium.

KW - Calcium

KW - Costamere

KW - Dystrophin

KW - Skeletal muscle injury

KW - Stretch-activated channels

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Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice

Abstract

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