Characterization of skeletal muscle in mouse models of osteogenesis imperfecta and myostatin deficiency

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Osteogenesis imperfecta (OI) is a heritable connective tissue disorder hallmarked by bone fragility resulting primarily from mutations in the pro[alpha]1(I) or pro[alpha]2(I) collagen genes. Muscle weakness is an often-reported, little-investigated concern of patients with OI. We examined the soleus (S), plantaris (P), gastrocnemius (G), tibialis anterior (TA) and quadriceps (Q) muscles of mice expressing mild (+/oim and +/G610C) and moderately severe (oim/oim) OI for evidence of inherent muscle pathology. Four month old oim/oim mouse muscles were generally smaller, had weaker muscles and an inability to sustain Po for the 300 ms testing duration for specific muscles; +/oim mice had a similar but milder skeletal muscle phenotype. Though four month old +/G610C mice had significant changes in the relative wet weights of the Q muscle (males) and S and G muscles (females) compared with same sex wt mice, their muscles were not weaker compared to their same sex wildtype (wt) counterparts. We next investigated the effects of exercise on skeletal muscle and bone. We found that oim/oim mice could not tolerate impact exercise but that +/oim mice responded similarly to exercise as wt mice, with modest improvements in bone biomechanical integrity. Lastly, we characterized the skeletal muscle in male and female myostatin (MSTN) deficient mice. Absence of functional MSTN during fetal development results in adult skeletal muscle hypertrophy and hyperplasia. Visible pathology in male Mstn -/- mice and decreased contractile strength relative to increased muscle weight suggest MSTN loss results in muscle impairment which is dose, sex and muscle dependent.