Abstract
Osteogenesis imperfecta (OI) is rare heritable connective tissue disorder that most often arises from mutations in the type I collagen genes, COL1A1 and COL1A2, displaying a range of symptoms including skeletal fragility, short stature, blue-gray sclera, and muscle weakness. Recent investigations into the intrinsic muscle weakness have demonstrated reduced contractile generating force in some murine models consistent with patient population studies, as well as alterations in whole body bioenergetics. Muscle weakness is found in approximately 80% of patients and has been equivocal in OI mouse models. Understanding the mechanism responsible for OI muscle weakness is crucial in building our knowledge of muscle bone cross-talk via mechanotransduction and biochemical signaling, and for potential novel therapeutic approaches. In this study we evaluated skeletal muscle mitochondrial function and whole-body bioenergetics in the heterozygous +/G610C (Amish) mouse modeling mild/moderate human type I/VI OI and minimal skeletal muscle weakness. Our analyses revealed several changes in the +/G610C mouse relative to their wildtype littermates including reduced state 3 mitochondrial respiration, increased mitochondrial citrate synthase activity, increased Parkin and p62 protein content, and an increased respiratory quotient. These changes may represent the ability of the +/G610C mouse to compensate for mitochondrial and metabolic changes that may arise due to type I collagen mutations and may also account for the lack of muscle weakness observed in the +/G610C model relative to the more severe OI models.