Ontogeny of Craniofacial Dysmorphology in Hypermuscular, GDF-8 (Myostatin) Deficient Mice

Objectives: Craniofacial dysmorphology can result from masticatory muscle hyperfunction. GDF-8 (myostatin), a growth factor in the TGF-ß superfamily, is a negative regulator of skeletal muscle growth. Mice homozygous for the myostatin null mutation demonstrate a substantial increase in masticatory musculature compared to normal mice. This study examined the onset and temporal relationship between hypermuscularity and craniofacial dysmorphology in myostatin deficient mice compared to wild-type, age-matched controls at four different ages. Methods: Sixty-two (32 wild-type and 30 GDF-8 -/- knockout) 1, 30 (weaning), 56, and 180 day old mice were used in the present study. Standardized lateral and dorsoventral radiographs were taken of each head. The radiographs were digitized, traced, and 30 landmarks were identified. Twenty-three measurements were made using Dolphin Image software. Significant mean differences were assessed using a group x age, two-way ANOVA. Results: Myostatin deficient mice had significantly smaller body (F group = 11.78; p<0.001) and masseter muscle weights (F group x age = 7.36; p<0.001) at 1 day of age and significantly greater weights at 30, 56 and 180 days of age compared to controls. Myostatin-deficient mice showed significantly (p<0.001) longer mandibles, shorter cranial bases, and different mandibular and cranial vault shape indices by 30 days of age. Significant correlations were noted between masseter muscle weight and mandibular body length (r=0.76; p<0.001), ramal height (r=0.84; p<0.001), and mandibular shape index (r=-0.57; p<0.001) at 30 days of age. Conclusions: Results from mice deficient in myostatin suggest that masticatory hypermuscularity-induced craniofacial anomalies are noted by weaning and become more pronounced with age. The mandible, cranial base, cranial vault, and face show a temporal sequence of compensatory growth related to masticatory hypermuscularity. These findings reiterate the important role that masticatory muscle function plays on the ontogeny of the cranial vault, cranial base, and most notably the mandible.

AR 049717