Calcium-dependent regulation of protein synthesis and degradation in muscle

Abstract

MUSCLE proteins undergo continuous intracellular turnover as do proteins in other cells^1,2. Furthermore, hormones, nutrients and work load can alter rates of protein synthesis and degradation in muscle, resulting in growth or atrophy of these tissues^1,2. In hereditary muscular dystrophies, where there is prominent wasting of the affected tissues, rates of both total protein synthesis and degradation are elevated^3–10. The immediate cause of this muscle atrophy is the imbalance resulting from an increase in protein degradation which exceeds a smaller enhancement in average protein synthesis. No simple explanation based on a defect in the response of dystrophic cells to known hormonal or nutritional factors has satisfactorily explained the elevation in the rates of both protein synthesis and degradation. We have now investigated the possible role of increased cellular Ca²⁺ as a mediator of such changes in protein metabolism based on other known structural and biochemical alterations in dystrophic muscles^11,12. Lesion(s) involving membranes in muscle as well as other cells occur in hereditary dystrophies, including the main human form, Duchenne dystrophy^11,12. One characteristic of the dystrophic plasma membrane seems to be an increased permeability to the high concentrations of Ca²⁺ normally present in extracellular fluid^11,12. In addition, studies have suggested a decreased ability of sarcoplasmic reticulum to sequester Ca²⁺ in dystrophic muscles^13,14. Thus, it is possible that increased Ca²⁺ might be responsible for the stimulation of both protein synthesis and degradation which occurs in these muscles. To test this idea, we have experimentally increased the uptake of external Ca²⁺ into rat muscles by using the divalent cation ionophore, A23187. The ability of this ionophore to increase the transport of Ca²⁺ across membranes has resulted in its application as a widely used tool for the study of many Ca²⁺-dependent cellular processes¹⁵. The experiments reported here demonstrate that increased movement of Ca²⁺ into muscle can produce effects which closely resemble dystrophic muscle and that the increased net catabolism can be reversed by certain factors.