GLUCOCORTICOIDS ACTIVATE THE ATP-UBIQUITIN-DEPENDENT PROTEOLYTIC SYSTEM IN SKELETAL-MUSCLE DURING FASTING

Glucocorticoids are essential for the increase in protein breakdown in skeletal muscle normally seen during fasting. To determine which prot eolytic pathway(s) are activated upon fasting, leg muscles from fed an d fasted normal rats were incubated under conditions that block or act ivate different proteolytic systems. After food deprivation (1 day), t he nonlysosomal ATP-dependent process increased by 250%, as shown in e xperiments involving depletion of muscle ATP. Also, the maximal capaci ty of the lysosomal process increased 60-100%, but no changes occurred in the Ca2+-dependent or the residual energy-independent proteolytic processes. In muscles from fasted normal and adrenalectomized (ADX) ra ts, the protein breakdown sensitive to inhibitors of the lysosomal or Ca2+-dependent pathways did not differ. However, the ATP-dependent pro cess was 30% slower in muscles from fasted ADX rats. Administering dex amethasone to these animals or incubating their muscles with dexametha sone reversed this defect. During fasting, when the ATP-dependent proc ess rises, muscles show a two- to threefold increase in levels of ubiq uitin (Ub) mRNA. However, muscles of ADX animals failed to show this r esponse. Injecting dexamethasone into the fasted ADX animals increased muscle Ub mRNA within 6 h. Thus glucocorticoids activate the ATP-Ub-d ependent proteolytic pathway in fasting apparently by enhancing the ex pression of components of this system such as Ub.