Development of a Diagnostic Method for Detecting Increased Muscle Protein Degradation in Patients with Catabolic Conditions

Abstract

Muscle atrophy in catabolic illnesses is due largely to accelerated protein degradation. Unfortunately, methods for detecting accelerated muscle proteolysis are cumbersome. The goal of this study was to develop a method for detecting muscle protein breakdown and assess the effectiveness of anticatabolic therapy. In rodent models of catabolic conditions, it was found that accelerated muscle protein degradation is triggered by activation of caspase-3. Caspase-3 cleaves actomyosin/myofibrils to form substrates for the ubiquitin-proteasome system and leaves a characteristic 14-kD actin fragment in the insoluble fraction of a muscle lysate. Muscle biopsies were obtained from normal adults and three groups of patients: 14 who were undergoing hip arthroplasty, 28 hemodialysis patients who were participating in exercise programs, and seven severely burned patients. In muscle of patients who were undergoing hip arthroplasty, the 14-kD actin fragment level was correlated (r ‫؍‬ 0.787, P < 0.01) with the fractional rate of protein degradation. In muscle of hemodialysis patients who were undergoing endurance exercise training, the 14-kD actin fragment decreased to values similar to levels in normal adults; strength training did not significantly decrease the actin fragment. Severely burned patients had increased muscle protein degradation and actin fragment levels, but the two measures were not significantly correlated. The experimental results suggest that the 14-kD actin fragment in muscle biopsies is increased in catabolic states and could be used in conjunction with other methods to detect and monitor changes in muscle proteolysis that occur in patients with mild or sustained increases in muscle proteolysis.

Effects of Oral Sodium Bicarbonate in Patients with CKD

“…Finally, we have speculated regarding a mechanistic explanation for our results based on the reduction in urinary nitrogen, although we are unable to definitively comment on nitrogen balance. Nitrogen balance should be confirmed by studies of alkali that include measures of lean body mass and direct assessment of muscle protein breakdown, which could include measurement of a 14-kDa actin fragment (37) in muscle biopsy specimens along with other changes in skeletal muscle at the cellular level.…”

Exercise-induced Biochemical Modifications in Muscle in Chronic Kidney Disease: Occult Acidosis as a Potential Factor Limiting the Anabolic Effect of Exercise

“…These problems arise from a number of factors 1 including inactivity, inflammation, anaemia, reduced muscle function and increased muscle protein catabolism 2 . There is growing evidence that exercise can provide benefits to patients with advanced CKD 1 such as improved exercise capacity, a reduction in cardiac risk factors, improved insulin sensitivity and glucose disposal, increased quality of life and reduced depression.…”

Nutritional influences on age-related skeletal muscle loss

“…Metabolic acidosis is one of the major causes of skeletal muscle loss in chronic kidney disease, and the mild metabolic acidosis that occurs within populations may also be relevant for loss of skeletal muscle (172)(173)(174) .…”

“…A number of mechanisms have been proposed for the loss of muscle mass with metabolic acidosis, largely derived from animal studies and studies on those with chronic kidney disease (172)(173)(174) . Metabolic acidosis potentially accelerates proteolysis and amino acid catabolism, probably through activation of caspase-3 and the ubiquitin proteasome system or via effects on the growth hormone/IGF-1 axis (97,(182)(183)(184)(185)(186) .…”