Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes.

Abstract

Metabolic acidosis often leads to loss of body protein due mainly to accelerated protein breakdown in muscle. To identify which proteolytic pathway is activated, we measured protein degradation in incubated epitrochlearis muscles from acidotic (NNH4CI-treated) and pair-fed rats under conditions that block different proteolytic systems. Inhibiting lysosomal and calcium-activated proteases did not reduce the acidosis-induced increase in muscle proteolysis. However, when ATP production was also blocked, proteolysis fell to the same low level in muscles of acidotic and control rats. Acidosis, therefore, stimulates selectively an ATP-dependent, nonlysosomal, proteolytic process.We also examined whether the activated pathway involves ubiquitin and proteasomes (multicatalytic proteinases). Acidosis was associated with a 2.5-to 4-fold increase in ubiquitin mRNA in muscle. There was no increase in muscle heat shock protein 70 mRNA or in kidney ubiquitin mRNA, suggesting specificity of the response. Ubiquitin mRNA in muscle returned to control levels within 24 h after cessation of acidosis. mRNA for subunits of the proteasome (C2 and C3) in muscle were also increased 4-fold and 2.5-fold, respectively, with acidosis; mRNA for cathepsin B did not change. These results are consistent with, but do not prove that acidosis stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasomedependent, proteolytic pathway. (J. Clin. Invest. 1994. 93: 2127-2133

High sodium chloride intake exacerbates immobilization-induced bone resorption and protein losses

“…Evidence exists that the additional protein losses we found with high NaCl intake can also be attributed to these NaCl-induced changes in the acid-base system. In rats, ammonium chloride-induced metabolic acidosis has been shown to 1) stimulate the ubiquitin-proteasome system for muscle proteolysis (8,49), and 2) activate branched-chain ketoacid dehydrogenase, leading to excessive oxidation of branched-chain amino acids in skeletal muscle (7,47). In contrast, our test subjects suffered from mild disturbances of acid-base balance within the normal range (69).…”

Regulation of Muscle Protein Degradation

“…In rat muscle with metabolic acidosis, uremia, or insulin deficiency, the Ub-P'some system is activated (16,18,22), which contributes to muscle protein loss (Figure 1, A and B). Interestingly, we found higher levels of atrogin-1/ MAFbx, the E3 enzyme that is closely associated with activation of protein degradation in muscle of rats with uremia as well as insulin deficiency (4,5).…”

“…Besides suppressing protein synthesis, our findings show that a reduced PI3K activity contributes to muscle atrophy via coordinated regulation of apoptotic and Ub-P'some systems, ultimately leading to protein degradation. It is tempting to speculate that the identified pathways account for the excessive muscle protein loss that occurs in conditions associated with insulin resistance, including metabolic acidosis, uremia, and conditions that increase glucocorticoids (11,16,27,(35)(36)(37)(38)(39).…”

“…As in uremia or metabolic acidosis, rats with insulin deficiency have suppressed PI3K activity in muscle, lose weight, and exhibit accelerated muscle proteolysis via activation of the Ub-P'some pathway (16,17,18,22,23). For these reasons and because insulin deficiency is more easily created and less expensive compared with models of metabolic acidosis or uremia, we studied how acute insulin deficiency affects apoptotic and Ub-P'some pathways in muscle (16,22). We confirmed that these rats lose weight and develop muscle atrophy; in the gastrocnemius muscle, we found that the cross-sectional area of muscle fibers (Figure 1, A and B) from four acutely diabetic rats (1390.6 Ϯ 109.2 2 ) was significantly less than that of four pair-fed control rats (2227.4 Ϯ 65.3 2 ; P Ͻ 0.001).…”

Evolving Practices in Critical Care and Potential Implications for Management of Acute Kidney Injury

“…Therefore, patients who are treated with steroids and who have AKI are likely to experience an abrupt increase in nitrogenous waste products, which may result in uremic complications and also diminish the ability to provide nutritional support. Hypercatabolism will be exacerbated further by acidosis, as a result of the effects on acidosis on the ubiquitin-proteasome pathway (43). Finally, the mineralocorticoid effects of methylprednisolone, prednisone, or fludrocortisone will promote fluid retention and volume overload by increasing sodium reabsorption in the distal tubule.…”