Nuclear bone morphogenetic protein 2 mutant mice exhibit slowed relaxation and a shift in the force frequency relationship in skeletal muscle

Conventional bone morphogenetic protein 2 (Bmp2) is a secreted growth factor characterized by its ability to induce bone and cartilage formation, and by its role in developmental processes such as axis formation, cardiac development, and neuronal differentiation. Recently, however, we have identified a novel form of Bmp2 (nBmp2) that is translated from an alternative start codon and is localized to the nucleus rather than being secreted. To study the function of nBmp2 in the nucleus, we generated mice bearing an nBmp2 mutation that prevents nuclear localization. Here we evaluate muscle performance in these mutant mice using in situ stimulation of the gastrocnemius, plantaris, soleus (GPS) muscle complex via the sciatic nerve. Specific peak tetanic force of the GPS muscle group was slightly higher in nBmp2 deficient mice compared to control mice (3.3 ± 0.1 and 3.1 ± 0.1 gm tension/mg muscle in mutant vs. control muscles, respectively, p>0.05). No significant differences were observed in the specific peak twitch force between groups. Muscle fatigue was examined using 2Hz twitch contractions for 10 min. The fatigue profiles for the two groups were essentially identical, but half relaxation times were significantly prolonged by up to a 42% increase in mutant muscles compared to control muscles (p<0.05). Further, force frequency analysis showed significantly elevated force production in mutant muscles compared to controls from 10 to 80 Hz stimulation frequency (p<0.01). These results suggest that nBmp2 plays an important role in maintaining normal intracellular transport of calcium during skeletal muscle contraction and relaxation. Grant support: NIH AR48839