Joint dysfunction and functional decline in middle age myostatin null mice

Abstract

Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn−/−), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3–6 months) to middle age (12–15 months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn−/− mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn−/− mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn−/− mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway.

Muscle strength is increased in mice that are colonized with microbiota from high-functioning older adults

“…Measures of physical function in mice included grip strength and treadmill endurance capacity, and were performed in a blinded manner. Forelimb gripping force by mice that were colonized with human fecal samples was measured with a computerized grip-strength meter (Columbus Instruments) based on the method of (Guo et al, 2016). Ten measurements were taken from each animal, and the average grip strength value was used for statistical analysis.…”

The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle

“…Genetic myostatin inhibition (i.e., through deletion or polymorphisms) results in mismatched muscle and bone growth compared to tendon and ECM development, which in higher order animals (cattle and dogs, including the GRippet (golden retriever muscular dystrophy [GRMD] crossed with the myostatin-deficient Whippet) canine model of DMD) results in joint instability and the reduced mass of many organs including lung and spleen [ 23 , 114 , 115 ]. In MSTN KO mice, functional decline is evident from young age and extends into middle age as measured through grip strength and treadmill exercise, and this coincides with significant ankle joint pathology involving bone, tendon, articular connective tissue and synovial fluid anomalies with inflammatory infiltrate [ 116 ]. The long-term consequences of such changes are unclear for pharmacological myostatin inhibitors but could ultimately be debilitating, particularly for DMD patients who already experience significant deterioration of respiratory function as disease progresses due to fibrosis of the diaphragm and accessory respiratory muscles.…”