Protein Metabolism and Acidosis
Introduction
Protein degradation and synthesis is a continuous process that functions to eliminate abnormal
proteins and to permit the regulation of cellular metabolism. The rate at which protein
degradation occurs varies with both the nutritional and hormonal state of cells. One of the key
determinants of protein function is acid-base homeostasis; deviations can have adverse
consequences on tissue and organ performance (1). In humans, increased systemic acidity
(acidosis) results in muscle wasting, due to increased protein degradation and is often
characterized by a negative nitrogen balance (2). Among rats, metabolic acidosis depresses
growth (3), increases urinary excretion of nitrogen and 3-methylhistidine -- suggesting increased
protein catabolism in skeletal muscle (4), and increases protein degradation in isolated muscle
(3). Acidosis has also been shown to accelerate intracellular protein degradation and oxidation of
branched-chain amino acids in human muscle (5). As the severity of metabolic acidosis
increases, protein catabolism accelerates (2).
Four major pathways by which intracellular protein degradation might occur exist: 1) lysosomal
proteases, 2) Ca2+-dependent proteases, 3) cytosolic ATP-independent proteases, and 4) cytosolic
ATP-dependent proteases. Although proteolysis must occur by one of the four known pathways,
the mechanism(s) by which acidosis stimulates proteolysis has just recently been investigated.
Control of Acidosis Induced Proteolysis
Medina et al. (6) reported skeletal muscle plays a critical role in the response to acidosis. When
rats were fed NH4Cl to induce metabolic acidosis and their muscles were depleted of ATP,
protein degradation decreased. These same researchers reported increased levels of mRNAs that
encoded for both ubiquitin and subunits of the proteasome during acidotic conditions.
Bailey et al. (7) found that protein degradation in muscles from rats experiencing acidosis was
approximately 40% higher than in normal rats. As in previous studies, depletion of ATP reduced
the rate of protein degradation induced by acidosis. Use of MG132, a proteasome inhibitor,
further indicated the involvement of the ubiquitin-proteasome pathway in the catabolic response
to acidosis. Similar to the depletion of ATP, addition of MG132 eliminated the difference in rate
of protein degradation between control and acidotic rats. This revealed that without ATP, acid
induced proteolysis did not occur. Thus, it can be concluded that acidosis stimulates muscle
protein degradation by activating the adenosine triphosphate-dependent pathway involving
ubiquitin and proteasomes. (Figures 1 and 2).
Bailey et al. (7) revealed that induced acidosis did not affect the quantity of GAPDH or g-actin
mRNAs transcribed from nuclei isolated from muscles or livers of acidotic vs. control rats. In
contrast, acidosis was associated with an increase in transcribed ubiquitin and C3 proteasome
subunit mRNAs in muscle. These data suggest that a gene transcription resulted in the increased
level of mRNAs encoding components of the ubiquitin-proteasome pathway. DeCoo (8) reported
a mutation in the tRNAVal G1642A gene was present in a patient with mitochondrial
encephalomyopathy, lactic acidosis, and stroke-like episosdes (MELAS) syndrome.
Can Metabolic Acidosis Be Corrected?
Halperin and Jungas (9) concluded that metabolic acidosis in chronic renal failure patients results
from impaired excretion of hydrogen ions derived principally from the metabolism of sulfurcontaining amino acids. Correction of metabolic acidosis may normalize amino acid oxidation
and increase the intracellular concentration of branched-chain amino acids. Graham et al. (10)
demonstrated that use of a high bicarbonate buffer in hemodialysis corrected acidotic conditions.
Brady et al. (11) concluded that oral supplementation of sodium bicarbonate (1 mEq/kg dry
weight/d) was effective in increasing serum bicarbonate and decreased whole body protein
degradation. Oral supplementation of sodium bicarbonate reduced protein degradation by
decreasing the activity of branched-chain ketoacid dehydrogenase in skeletal muscle and may
contribute to an increase in body mass.
Relationship Between Metabolic Acidosis and Growth
Metabolic acidosis in livestock results from the accumulation of lactic acid in the rumen, usually
caused by the consumption of carbohydrates with high ruminal availability (12). As highly
fermentable carbohydrate is introduced to the diet, ruminal volatile fatty acid production
increases as pH starts to decline (Figure 3). Production of acids outside the critical pH threshold
of the rumen -- < 5.0 during acute acidosis and < 5.5 during subclinical acidosis (12) -- results in
altered microbial growth rates, shifts in ruminal populations, and significantly influences the
systemic metabolic state.
As previously discussed, accumulation of acid impairs nitrogen utilization, protein breakdown,
and stimulates proteolysis. Thus, unless protein synthesis increased in proportion to proteolysis,
protein accretion and growth would decrease. However, until recently, the effect of metabolic
acidosis on protein metabolism in ruminants had not been investigated. Using ovine fetuses,
Milley (13) measured the effects of acidosis on protein balance and found that fetal leucine was
released into the fetal plasma from breakdown of endogenous fetal proteins during acidosis. Fetal
protein accretion diminished as a result of the increased rate of proteolysis and no additional
protein synthesis.
Summary
Acidosis, whether a result of chronic renal failure, excess intake of carbohydrate high in rumen
availability, or induced by some other mechanism, increases proteolysis of skeletal muscle and
decreases nitrogen retention. Consequently, accretion of muscle mass is reduced. However,
acidosis induced protein and amino acid degradation is dependent upon activation of the ATPdependent pathway involving ubiquitin and proteasomes as well as increased activity of
branched-chain ketoacid dehydrogenase in skeletal muscle. Sodium bicarbonate may be fed to
increase blood buffering capacity, decrease protein degradation, and enhance protein accretion.
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