Long-term Physical Inactivity Exacerbates Hindlimb Unloading-induced Soleus Muscle Atrophy In Young Rats

Physical inactivity (sedentary lifestyle) in adulthood increases a degree of aging-related skeletal muscle weakness; however, it has been unclear whether long-term physical inactivity in childhood exacerbates subsequent disuse-induced skeletal muscle atrophy. PURPOSE: This study investigated the effects of long-term physical inactivity in childhood on subsequent hindlimb unloading-induced muscle atrophy in rat soleus muscle. METHODS: Forty-eight 3-week-old male Wistar rats were assigned randomly into control (CON, n = 24) or physical inactivity (IN, n = 24) groups. Rats in the IN group were housed in a narrow cage with half of the usual floor space to limit the range of their movement. After 8 weeks (12-week-old), the rats (CON & IN) were exposed to hindlimb unloading. The soleus muscles were quickly removed before (0 d, n = 6/each group), 1 day (1d, n = 6/each group), 3 days (3d, n = 6/each group) and 7 days (7d, n = 6/each group) after unloading. mRNA and protein levels were determined by RT-PCR and Western blot analysis. Statistical significance was established at p<0.05. RESULTS: Although 7-days of hindlimb unloading significantly decreased soleus muscle weight (CON; -28%, IN; -33%, p<0.001), the decrease was drastically in IN group (Inactivity × Unloading, p = 0.0009). A significant interaction between inactivity and unloading (p<0.01) was observed on the HDAC4 and NF-kB protein expressions. The HDAC4 and NF-kB expressions in the IN group increased significantly 1 day after onset of hindlimb unloading (CON; 1.4 and 1.2, IN; 5.1 and 2.7 fold change from each 0d, respectively). Moreover, their downstream targets Myogenin and MuRF1 mRNA levels were upregulated by long-term physical inactivity (Inactivity, p<0.05). CONCLUSIONS: Our data suggest that long-term physical inactivity exacerbates hindlimb unloading-induced disuse muscle atrophy in young rat soleus muscle, which may be mediated by HDAC4 and NF-kB-induced MuRF1 mRNA upregulation. Supported by JSPS KAKENHI Grant Number 17K01765.