Frailty in the healthy elderly has become a widespread problem central to the care of geriatric populations. It causes impaired mobility and an increased susceptibility to muscle injury, especially from falls. This leads to a decrease in the quality of life and an increase in the cost of health care. The major factors contributing to frailty are age-associated loss of muscle mass and function, which, correlates strongly to increased mortality, particularly in men over the age of 60. The loss of muscle mass with increased age will eventually affect all people, because it is not simply a matter of declining physical activity but rather of biological changes associated with advancing age. The overall goal of this proposal is to define cellular and molecular mechanisms of actions of Id2 in muscle growth in aging. This information is critical for designing appropriate strategies to reduce frailty and improve function and independence in the elderly. Our pilot data suggest that aging is associated with increased levels of Id2 mRNA and protein, and this is correlated to increased apoptosis in muscles of old animals. This project consists of three integrated parts: [1] To identify whether Id2 is an important determinant of the increase in apoptosis in aging muscle, and therefore contributes to the decrease in muscle mass and attenuation of hypertrophy in response to overload that has been documented in aging (Aim 1 and 2). We will also investigate the mechanisms of action of Id2 to determine its' role in regulating muscle differentiation and apoptosis in vitro (Aim 1). [2] To determine if skeletal muscles of aged animals have reduced levels of apoptosis if Id2 is inhibited in vivo (Aim 2). [3] To determine if phosphorylation of Id2 regulates the function of this protein in muscles cells of aged animals in vitro and in vivo. We will manipulate Id2 levels and the phosphorylation status of Id2 in muscle cell cultures and muscles of aged animals under conditions of overload and unloading. Because the Id2 responses and levels may be regulated, in part by the absolute load placed on the experimental muscles, we will use two in vivo models of overload in aged animals. The first is a functional rodent model of overload that is highly dependent upon neural activity, body weight and ambulation of the animal. A second, is an avian model of stretch overload. This model is less dependent upon the muscle's innervation status, and the effects of Id2 can be compared under identical loading or unloading conditions in young adult or aged animals. The data that will be obtained in this project provide the potential for developing new strategies for reducing apoptosis, and improving or preserving muscle mass with aging with the goal to reduce the effects of frailty.
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