Functional responses of uremic single skeletal muscle fibers to redox imbalances

Background: The exact causes of skeletal muscle weakness in chronic kidney disease (CKD) remain unknown with uremic toxicity and redox imbalances being implicated. To understand whether uremic muscle has acquired any sensitivity to acute redox changes we examined the effects of redox disturbances on force generation capacity. Methods: Permeabilized single psoas fibers (N = 37) from surgically induced CKD (UREM) and sham-operated (CON) rabbits were exposed to an oxidizing (10 mM Hydrogen Peroxide, H2O2) and/or a reducing [10 mM Dithiothreitol (DTT)] agent, in a blind design, in two sets of experiments examining: A) the acute effect of the addition of H2O2 on maximal (pCa 4.4) isometric force of actively contracting fibers and the effect of incubation in DTT on subsequent reactivation and force recovery (N = 9 CON; N = 9 UREM fibers); B) the effect of incubation in H2O2 on both submaximal (pCa 6.2) and maximal (pCa 4.4) calcium activated isometric force generation (N = 9 CON; N = 10 UREM fibers). Results: Based on cross-sectional area (CSA) calculations, a 14 % atrophy in UREM fibers was revealed; thus forces were evaluated in absolute values and corrected for CSA (specific force) values. A) Addition of H2O2 during activation did not significantly affect force generation in any group or the pool of fibers. Incubation in DTT did not affect the CON fibers but caused a 12 % maximal isometric force decrease in UREM fibers (both in absolute force p = 0.024, and specific force, p = 0.027). B) Incubation in H2O2 during relaxation lowered subsequent maximal (but not submaximal) isometric forces in the Pool of fibers by 3.5 % (for absolute force p = 0.033, for specific force p = 0.019) but not in the fiber groups separately. Conclusions: Force generation capacity of CON and UREM fibers is affected by oxidation similarly. However, DTT significantly lowered force in UREM muscle fibers. This may indicate that at baseline UREM muscle could have already been at a more reduced redox state than physiological. This observation warrants further investigation as it could be linked to disease-induced effects.