Beta‐GPA‐induced changes in mitochondrial biogenesis are associated with a muscle type‐dependent decrease in RIP140

Abstract

Beta‐guanidopropionic acid (β‐GPA) is a creatine analogue that leads to reductions in ~P concentrations and increases in markers of mitochondrial content in rodent skeletal muscle. Prior evidence attributes these changes to activation of the 5'AMP pathway; however data suggest RIP140, a negative downstream regulator of PPAR gamma co‐activator 1 alpha (PGC‐1α), is a likely player in the regulation of mitochondrial biogenesis (MB). The aim of this study was to determine if β‐GPA feeding decreases RIP140 protein in skeletal muscle in a fiber type‐specific manner and if it is associated with an increase in mitochondrial content. Male Wistar rats were fed a semi‐purified diet supplemented with (n=12) or without (n=12) 1% β‐GPA for 6 weeks. β‐GPA feeding induced skeletal muscle MB in tricep as shown by increases in CORE1 and COXIV protein and citrate synthase activity. In contrast, no such changes were seen in soleus from β‐GPA‐fed rats. β‐GPA feeding led to a ~75% increase in PGC1α messenger RNA expression in tricep and ~140% increase in soleus. RIP140 protein decreased ~40% in tricep while it was unchanged in the soleus. In summary, β‐GPA feeding led to decreases in RIP140 in rat tricep only, correlating to increases in MB in only this muscle type. This suggests that RIP140 may play a key role in regulating MB downstream of PGC1α and provides a mechanism for fiber type differences in muscle adaptation.Supported by NSERC