Role of myostatin in regulating chondrocyte and musculoskeletal function in aging mice

Thesis (Ph.D.)--Boston UniversityMyostatin (mstn) belongs to the TGF-β family and is best known as a negative regulator of muscle growth. Hypermuscularity in mstn knockout mice has been widely recognized and numerous mstn inhibitors are in development to treat sarcopenia associated with aging and muscle wasting associated with chronic illness. To determine the health impact of long term mstn deficiency on physical performance, myostatin null (mstn-/-) mice were studied at three aging time points (5, 15, 22 months). Long term complete inhibition of myostatin was hypothesized to prevent the decline in physical performance expected with aging. The data disproves this hypothesis. While increased muscle was observed in the mstn-/- and the mice demonstrated an expected grip strength advantage at 5 months, by 15 and 22 months the overall grip strength was reduced with no significant difference compared to controls. Horizontal and vertical ambulatory activity at each aging time point showed a significantly decreased or a decreased trend when compared with age-matched wild type controls. Furthermore, the mstn-/- mice treadmill endurance was significantly less at 5 and 22 months and demonstrated a decreased trend at 15 months when compared to age-matched controls. Overall, long term myostatin deletion does not aid in the maintenance of overall physical performance as the animal ages. Since prior studies had also shown that myostatin affected both bone mass, cartilage development and skeletal tissue repair the effects of myostatin deletion were next examined relative to skeletal tissue structure and function. Micro Computerized Tomography (MicroCT) analysis showed increased size and ossification of the meniscus surrounding the knee, ectopic ossification surrounding the tarsal bones and extra ossification in joints between manus carpal bones in the myostatin null mice. These studies showed that this ectopic calcification increased with aging. Corresponding histology of 22 month old mstn-/- mice demonstrated increased fibrocartilage proliferation of the meniscus and loss of the tibial articular cartilage. Our current data suggests long term complete deletion of myostatin increases proliferation and differentiation of fibrocartilage and reduces articular cartilage maintenance leading to impaired joint function and an overall reduction in physical performance