The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway.

Abstract

Chronic renal failure (CRF) is associated with negative nitrogen balance and loss of lean body mass. To identify specific proteolytic pathways activated by CRF, protein degradation was measured in incubated epitrochlearis muscles from CRF and sham-operated, pair-fed rats. CRF stimulated muscle proteolysis, and inhibition of lysosomal and calcium-activated proteases did not eliminate this increase. When ATP production was blocked, proteolysis in CRF muscles fell to the same level as that in control muscles. Increased proteolysis was also prevented by feeding CRF rats sodium bicarbonate, suggesting that activation depends on acidification. Evidence that the ATP-dependent ubiquitinproteasome pathway is stimulated by the acidemia of CRF includes the following findings: ( a ) An inhibitor of the proteasome eliminated the increase in muscle proteolysis; and ( b ) there was an increase in mRNAs encoding ubiquitin (324%) and proteasome subunits C3 (137%) and C9 (251%) in muscle. This response involved gene activation since transcription of mRNAs for ubiquitin and the C3 subunit were selectively increased in muscle of CRF rats. We conclude that CRF stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent pathway. The mechanism depends on acidification and increased expression of genes encoding components of the system. These responses could contribute to the loss of muscle mass associated with CRF. (

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).…”

“…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).…”

Effects of Oral Sodium Bicarbonate in Patients with CKD

“…Recently, studies have begun to assess its contribution to the morbidity experienced by patients with nondialysis-dependent CKD (2)(3)(4). Acidosis may contribute to loss of muscle mass through abnormal muscle signaling, IGF-1 dysregulation, insulin resistance, and inflammation (5)(6)(7)(8)(9). Animal models have shown that acidosis promotes muscle proteolysis through impaired phosphatidylinositol 3-kinase (PI3K)/Akt signaling in skeletal muscle (5,6).…”

“…Acidosis may contribute to loss of muscle mass through abnormal muscle signaling, IGF-1 dysregulation, insulin resistance, and inflammation (5)(6)(7)(8)(9). Animal models have shown that acidosis promotes muscle proteolysis through impaired phosphatidylinositol 3-kinase (PI3K)/Akt signaling in skeletal muscle (5,6). Notably, this pathway mediates the anabolic and anticatabolic effects of IGF-1 and insulin (10), implicating acidosis as one cause of the resistance to both hormones seen in uremia (6,8).…”