5-aminoimidazol-4-karboksamid ribonükleotit (Aicar)'in (Kardiyo)miyopati üzerindeki etkileri

Healthy mitochondria are essential for maintaining cellular homeostasis, in addition to their well-known role in ATP production. Dysfunctional mitochondria cause mitochondrial diseases, primarily affecting tissues that require high energy levels such as cardiac and skeletal muscle. To model mitochondrial cardiomyopathy and mitochondrial myopathy, we used mice with tissue-specific knockout of mitochondrial aspartyl-tRNA synthetase (DARS2) in a heart- and skeletal muscle-specific (hmKO), and skeletal muscle-specific (mKO) manner, respectively. The study aimed to alleviate the symptoms of these models by daily injections of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which activate AMPK and increase mitochondrial mass. There was no mitigation of phenotypic symptoms; however, at the molecular level, we detected tissue-specific responses by comparing the expression of markers for mitochondrial biogenesis, metabolic activity, mitochondrial integrated stress response ISRmt, and macro-autophagy in the heart and skeletal muscle of the hmKO and mKO mice, respectively. We report an increase in mitochondrial biogenesis markers, a boost in glucose and lipid metabolism, increased ATP levels, and an increase in macro-autophagy in the skeletal muscle of mKO mice. However, in the hearts of the hmKO mice, there was a decrease in mitochondrial biogenesis markers, a shift towards glucose metabolism, decreased ATP levels, and a potential blockade to macro-autophagy. We conclude that the differential responses to AICAR between tissues may be attributed to the functional status of macro-autophagy.