Skeletal muscle transcriptome alterations associated with ketosis in postpartum dairy cows

Excessive body fat mobilization during the transition period overwhelms hepatic fatty acid (FA) oxidative capacity, leading to increased ketone body production and ketosis in dairy cows. Skeletal muscle (SM) has been shown to uptake and oxidize FA via mitochondrial β-oxidation and may play a crucial role in counteracting hepatic FA overload. However, the role of SM in the pathogenesis of ketosis remains unclear. The objective of this study was to investigate transcriptomic alterations in the SM of postpartum dairy cows diagnosed with ketosis and identify genes and pathways potentially involved in the pathogenesis of the disease. Multiparous Holstein cows within 7 d in milk (DIM) were classified based on their blood β-hydroxybutyrate (BHB) concentrations as ketosis (BHB ≥1.3 mmol/L and reduced rumination; n = 15) and controls (BHB ≤1.1 mmol/L with no clinical signs; n = 15). On the day of enrollment, a biopsy from the external oblique muscle was collected and later processed for RNA sequencing. Differential expression analysis identified 3,796 differentially expressed genes (DEG), with 1,692 upregulated and 2,104 downregulated in the ketosis group relative to controls. Transcriptomic signatures of SM during ketosis revealed the upregulation of genes involved in protein synthesis, folding, and degradation, alongside downregulation of genes involved in mitochondrial energy production, extracellular matrix synthesis and remodeling, and muscle structure and contraction. In addition, we observed the downregulation of several genes involved in FA β-oxidation and ketone catabolism. Although these findings provide evidence of extensive transcriptional remodeling of SM during ketosis, further studies are warranted to determine the biological significance of these alterations and whether they precede, accompany, or are a result of the disorder.