Exercise alters and ß-alanine combined with exercise augments histidyl dipeptide levels and scavenges lipid peroxidation products in human skeletal muscle.

Carnosine and anserine are dipeptides synthesized from histidine and ß-alanine by carnosine synthase (ATPGD1). These dipeptides, present in high concentration in the skeletal muscle, form conjugates with lipid peroxidation products such as 4-hydroxy trans-2-nonenal (HNE). Although skeletal muscle levels of these dipeptides could be elevated by feeding ß-alanine, it is unclear how these dipeptides and their conjugates are affected by exercise training with or without ß-alanine supplementation. We recruited 20 physically active men, who were allocated to either ß-alanine or placebo-feeding group matched for peak oxygen consumption, lactate threshold, and maximal power. Participants completed 2 wk of a conditioning phase followed by 1 wk of exercise training, a single session of high-intensity interval training (HIIT), followed by 6 wk of HIIT. Analysis of muscle biopsies showed that the levels of carnosine and ATPGD1 expression were increased after CPET and decreased following a single session and 6 wk of HIIT. Expression of ATPGD1 and levels of carnosine were increased upon ß-alanine-feeding after CPET, whereas ATPGD1 expression decreased following a single session of HIIT. The expression of fiber type markers myosin heavy chain I and IIa remained unchanged after CPET. Levels of carnosine, anserine, carnosine-HNE, carnosine-propanal, and carnosine-propanol were further increased after 9 wk of ß-alanine supplementation and exercise training but remained unchanged in the placebo-fed group. These results suggest that carnosine levels and ATPGD1 expression fluctuates with different phases of training. Enhancing carnosine levels by ß-alanine feeding could facilitate the detoxification of lipid peroxidation products in the human skeletal muscle.NEW & NOTEWORTHY Carnosine synthase expression and carnosine levels are altered in the human skeletal muscle during different phases of training. During high-intensity interval training, ß-alanine feeding promotes detoxification of lipid peroxidation products and increases anserine levels in the skeletal muscle.

Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice.

Pathological cardiac hypertrophy is associated with the accumulation of lipid peroxidation-derived aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and acrolein in the heart. These aldehydes are metabolized via several pathways, of which aldose reductase (AR) represents a broad-specificity route for their elimination. We tested the hypothesis that by preventing aldehyde removal, AR deficiency accentuates the pathological effects of transverse aortic constriction (TAC). We found that the levels of AR in the heart were increased in mice subjected to TAC for 2 weeks. In comparison with wild-type (WT), AR-null mice showed lower ejection fraction, which was exacerbated 2 weeks after TAC. Levels of atrial natriuretic peptide and myosin heavy chain were higher in AR-null than in WT TAC hearts. Deficiency of AR decreased urinary levels of the acrolein metabolite, 3-hydroxypropylmercapturic acid. Deletion of AR did not affect the levels of the other aldehyde-metabolizing enzyme - aldehyde dehydrogenase 2 in the heart, or its urinary product - (N-Acetyl-S-(2-carboxyethyl)-l-cystiene). AR-null hearts subjected to TAC showed increased accumulation of HNE- and acrolein-modified proteins, as well as increased AMPK phosphorylation and autophagy. Superfusion with HNE led to a greater increase in p62, LC3II formation, and GFP-LC3-II punctae formation in AR-null than WT cardiac myocytes. Pharmacological inactivation of JNK decreased HNE-induced autophagy in AR-null cardiac myocytes. Collectively, these results suggest that during hypertrophy the accumulation of lipid peroxidation derived aldehydes promotes pathological remodeling via excessive autophagy, and that metabolic detoxification of these aldehydes by AR may be essential for maintaining cardiac function during early stages of pressure overload.