Identification of cardio‐metabolic protective myokines from Akt1‐mediated hypertrophic glycolytic muscles

Glycolytic skeletal muscle fibers are preferentially lost during aging and many cachectic states such as diabetes or cancer. We have previously constructed a murine model, where a constitutively‐active Akt1 transgene can be conditionally activated specifically in glycolytic skeletal muscle fibers. Induction of Akt1 transgene in skeletal muscles induced significant muscle hypertrophy and transcriptional reprogramming that mimics the effects of resistance exercise training. Employing this murine system in diet induced‐obesity, we have previously shown improvements on insulin sensitivity, fat mass and liver transcription profile. We therefore hypothesized that skeletal muscle growth improves diet‐induced metabolic syndromes via secretion of small peptides or cytokines, referred to as myokines. To identify novel myokines with beneficial cardiovascular and metabolic effects, we employed polyA(+) RNA sequencing for gastrocnemius muscles with or without Akt1 transgene activation from mice on normal chow and 15weeks of high fat diet (HFD). In silico analysis identified gene expression changes and networks altered in muscles metabolically challenged by HFD. We also identified an array of putative myokines that was dysregulated in HFD but restored by Akt1‐transgene activation induced muscle growth. Our data provides an extensive characterization of muscle transcriptome during diet‐induced obesity and contributes to better understanding of muscle‐organ crosstalk mediated by myokines.