Upregulation of Hallmark Muscle Genes Protects GneM743T/M743T Mutated Knock-In Mice From Kidney and Muscle Phenotype.

backgroundMutations in GNE cause a recessive, adult onset myopathy characterized by slowly progressive distal and proximal muscle weakness. Knock-in mice carrying the most frequent mutation in GNE myopathy patients, GneM743T/M743T, usually die few days after birth from severe renal failure, with no muscle phenotype. However, a spontaneous sub-colony remains healthy throughout a normal lifespan without any kidney or muscle pathology.

objectiveWe attempted to decipher the molecular mechanisms behind these phenotypic differences and to determine the mechanisms preventing the kidney and muscles from disease.

methodsWe analyzed the transcriptome and proteome of kidneys and muscles of sick and healthy GneM743T/M743T mice.

resultsThe sick GneM743T/M743T kidney was characterized by up-regulation of extra-cellular matrix degradation related processes and by down-regulation of oxidative phosphorylation and respiratory electron chain pathway, that was also observed in the asymptomatic muscles. Surprisingly, the healthy kidneys of the GneM743T/M743T mice were characterized by up-regulation of hallmark muscle genes. In addition the asymptomatic muscles of the sick GneM743T/M743T mice showed upregulation of transcription and translation processes.

conclusionsOverexpression of muscle physiology genes in healthy GneM743T/M743T mice seems to define the protecting mechanism in these mice. Furthermore, the strong involvement of muscle related genes in kidney may bridge the apparent phenotypic gap between GNE myopathy and the knock-in GneM743T/M743T mouse model and provide new directions in the study of GNE function in health and disease.