Osteogenesis imperfecta (OI), also commonly referred to as brittle bone disease, is a heritable connective tissue disorder occurring in roughly 1:15,000 births. OI arises as a result of mutations in the type I collagen genes, COL1A1 and COL1A2, approximately 85 [percent] of the time with the remaining 15 [percent] of cases arising from mutations in genes involved in posttranslational modification of type I collagen, osteoblast maturation or mineralization. OI is a heterogeneous disorder that can be classified into four major types with severity ranging from perinatal lethality to premature osteoporosis. As the name suggests, osteogenesis imperfecta, literally translating to imperfect bone formation, results in bone fragility with patients often experiencing many fractures throughout their lifetime. While bone fragility is the most prominent manifestation of OI, skeletal muscle weakness, cardiopulmonary complications, short stature, and craniofacial abnormalities are also common. There is currently no cure for OI and therapeutic options rely on mitigating symptoms, primarily through the use of bone anti-resorptive agents referred to as bisphosphonates. Although, current treatment options focus solely on bone health, skeletal muscle weakness is a common manifestation in OI, where 80 [percent] of patients with mild OI experience muscle force deficits, and with even higher percentages in patients with more clinically severe OI. Historically, OI muscle weakness was largely attributed to inactivity with recent studies highlighting its inherent nature in both patients and mouse models. Studies investigating the mechanisms by which skeletal muscle weakness arises in OI are limited, despite the large prevalence. My research sought to better understand OI muscle weakness primarily through the investigation of mitochondrial health in a mouse modeling a severe human type III OI (oim/oim), as mitochondria are important regulators of energy metabolism and overall cell health. We hypothesized that oim/oim mice, exhibiting severe skeletal muscle weakness would exhibit mitochondrial dysfunction suggesting a correlation between skeletal muscle and mitochondrial function. To test this hypothesis, we assessed mitochondrial function and content in the oim/oim mouse. One of our major findings was the observation that oim/oim mice exhibit [greater than] 50 [percent] reductions in gastrocnemius mitochondrial respiration rates relative to wildtype littermates. Additionally, we found that citrate synthase activity in oim/oim isolated gastrocnemius mitochondria was reduced relative to wildtype littermates. Furthermore, to determine if skeletal muscle mitochondrial function correlated with skeletal muscle severity, we evaluated mitochondrial respiration in a mouse model of mild OI (+/oim). We did not find differences between +/oim and WT gastrocnemius mitochondrial respiration suggesting that mitochondrial function does correlate with skeletal muscle function. Moreover, we did not observe changes in mitochondrial respiration in oim/oim liver and heart suggesting the mitochondrial dysfunction is not global in the oim/oim mouse. Additionally, we sought to investigate whole body metabolic alterations, as skeletal muscle comprises roughly 50 [percent] of body mass and is a significant contributor to the body's resting metabolic rate. We hypothesized that skeletal muscle mitochondrial dysfunction in the oim/oim mouse would lead to changes in metabolic parameters including altered substrate utilization, altered body composition, and changes in energy expenditure. Interestingly, we did not observe changes in substrate utilization, although we did note increased energy expenditure and subtle changes in body composition with oim/oim animals exhibiting reduced percentages of fat mass and increased percentages of lean mass relative to wildtype littermates. Overall, my research was the first to implicate mitochondrial dysfunction in the pathophysiology of OI using a mouse model of severe OI. This work has led to numerous studies in other mouse models evaluating mitochondrial function and energy metabolism. While there is more work to be done to further understand the mechanisms and correlation between mitochondrial dysfunction and skeletal muscle weakness in OI, this novel finding has initiated a new area of research in OI and has contributed to the overall understanding of OI muscle weakness.
Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications