The impact of muscle inactivity and exercise training on histidine-dipeptide homeostasis in rat skeletal muscle

Evidence suggests that muscle activity can affect muscle carnosine, but the results are mixed. To address this question, we investigated muscle carnosine under two extremes of the muscle activity-inactivity spectrum. Forty-five male Wistar rats were divided into three groups: immobilization (<i>n</i> = 16), SHAM control (<i>n</i> = 14), and immobilization + exercise (<i>n</i> = 15). In the immobilized groups, one side was submitted to a sciatic nerve sectioning surgery, with the opposite side being submitted to a SHAM control surgery, creating four experimental conditions: denervated (DEN), SHAM active control (SHAM), denervated + exercise (DEN + Ex), and SHAM + exercise (SHAM + Ex). The immobilization period was 12 wk, and the swimming training period was 10 wk (4 times per week, up to 30 min per session). The <i>tibialis anterior</i> (TA) and soleus muscles from both sides were assessed for carnosine and anserine contents, total histidine-dipeptides (HCDs), cross-sectional fiber area (CSA), and fiber type distribution. Contractile function was determined ex vivo in the <i>extensor digitorum longus</i>, and the expression of the <i>Carns1</i>, <i>Cndp2</i>, and <i>TauT</i> genes was determined with real-time polymerase chain reaction in TA. Physical inactivity drastically reduced muscle mass, contractile function, and fiber CSA. Long-term postdenervation muscle paralysis reduced muscle carnosine and anserine content, which was not dependent on diet, age, sex, or fiber type. This demonstrates that muscle inactivity is a strong modulator of muscle HCD content, at least under extreme conditions. Gene expression was not significantly altered in any of the experimental conditions. Exercise training, on the other hand, did not affect muscle HCDs and may be a less potent regulator of muscle HCD content.<b>NEW & NOTEWORTHY</b> This study demonstrated that an extreme model of muscle inactivity in rats (i.e., 12 wk of hindlimb paralysis following denervation) resulted in a substantial decline in muscle carnosine and anserine, which occurred irrespective of fiber type shift. Conversely, exercise training had no effect on histidine-dipeptide content. These findings, along with previously published studies, reinforce the notion that muscle inactivity is an important modulator of histidine-dipeptide homeostasis in skeletal muscle.