AbstractThis study investigated the impact of long‐term physical inactivity on hepatic cytoprotective‐ and inflammatory‐related protein expressions in young rats and the subsequent apoptotic response during microgravity stress simulated by tail suspension. Four‐week‐old male Wistar rats were randomly assigned to the control (CT) and physical inactivity (IN) groups. The floor space of the cages provided to the IN group was reduced to half of that provided to the CT group. After 8 weeks, rats in both groups (n= 6–7) underwent tail suspension. Their livers were harvested immediately before (0 day) or 1, 3, and 7 days after tail suspension. Levels of hepatic heat shock protein 72 (HSP72), an anti‐apoptotic protein, reduced over 7 days of tail suspension in the IN group than in the CT group (p< 0.01). Fragmented nucleosomes in the cytoplasmic fraction of the liver, an apoptotic index, were drastically increased by physical inactivity and tail suspension, and this change was significantly greater after 7 days of tail suspension in the IN group than in the CT group (p< 0.01). The apoptotic response was accompanied by the upregulation of pro‐apoptotic proteins (cleaved caspase‐3 and ‐7). Moreover, the levels of other pro‐apoptotic proteins (tumor necrosis factor‐1α and histone deacetylase 5) were also significantly higher in the IN than in the CT group (p< 0.05). Our results indicated that 8 weeks of physical inactivity decreased hepatic HSP72 levels and promoted hepatic apoptosis during the subsequent 7 days of tail suspension.