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In vivo characterization of the role of tissue‐specific translation elongation factor 1 A 2 in protein synthesis reveals insights into muscle atrophy
Author(s) -
Doig Jennifer,
Griffiths Lowri A.,
Peberdy David,
Dharmasaroja Permphan,
Vera Maria,
Davies Faith J. C.,
Newbery Helen J.,
Brownstein David,
Abbott Catherine M.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12554
Subject(s) - denervation , genetically modified mouse , biology , atrophy , muscle atrophy , downregulation and upregulation , transgene , skeletal muscle , endocrinology , in vivo , medicine , protein biosynthesis , phenotype , translation (biology) , microbiology and biotechnology , messenger rna , genetics , gene
Translation elongation factor 1A2 ( eEF 1A2), uniquely among translation factors, is expressed specifically in neurons and muscle. e EF 1 A 2‐null mutant wasted mice develop an aggressive, early‐onset form of neurodegeneration, but it is unknown whether the wasting results from denervation of the muscles, or whether the mice have a primary myopathy resulting from loss of translation activity in muscle. We set out to establish the relative contributions of loss of e EF 1 A 2 in the different tissues to this postnatal lethal phenotype. We used tissue‐specific transgenesis to show that correction of e EF 1 A 2 levels in muscle fails to ameliorate the overt phenotypic abnormalities or time of death of wasted mice. Molecular markers of muscle atrophy such as Fbxo32 were dramatically upregulated at the RNA level in wasted mice, both in the presence and in the absence of muscle‐specific expression of e EF 1 A 2, but the degree of upregulation at the protein level was significantly lower in those wasted mice without transgene‐derived expression of e EF 1 A 2 in muscle. This provides the first in vivo confirmation that e EF 1 A 2 plays an important role in translation. In spite of the inability of the nontransgenic wasted mice to upregulate key atrogenes at the protein level in response to denervation to the same degree as their transgenic counterparts, there were no measurable differences between transgenic and nontransgenic wasted mice in terms of weight loss, grip strength, or muscle pathology. This suggests that a compromised ability fully to execute the atrogene pathway in denervated muscle does not affect the process of muscle atrophy in the short term.