Effects of Exercise, Caloric Restriction and Subsequent Weight Regain Following the Loss of Ovarian Function on Mitochondrial Respiration

Exercise counters the biological drive to regain weight after weight loss, both by reducing the drive to overfeed and by increasing expended energy beyond the cost of the exercise bout. In the present study, we examined the effect of exercise in female rats after the loss of ovarian function, when the drive to gain weight is known to be exacerbated. More specifically, the impact of caloric restriction and exercise were studied in isolated skeletal muscle mitochondria following surgically induced menopause (ovariectomy=OVX) and weight regain. Diet induced obese female rats were weight reduced (15% body weight) by restricting caloric intake, with (EX) or without (SED) a daily bout of treadmill exercise (60 min/day, 6 days/week, 15 m/min). The rats were then surgically ovariectomized (OVX), and allowed ad libitum access for 6 weeks. An ad libitum (AL) group of obese rats that did not undergo caloric restriction, were ovariectomized and included as controls. Mitochondria were isolated from the hindlimb skeletal muscle (triceps surae) and subjected to several different substrates and substrate combinations. Mitochondrial respiratory capacity was determined under the following substrate conditions: pyruvate + malate (P+M), pyruvate + palmitoyl carnitine (P+PC+M), palmitoyl carnitine+malate (PC+M), and glutamate + malate (G+M). Following unrestrained feeding for 6 weeks, the mitochondrial capacity to oxidize P+M was reduced roughly 40% in lean SED and 50% in obese SED compared to lean AL and obese AL, respectively. Similarly, a decrease of about 25% in mitochondrial capacity to oxidize P+PC+M was observed in both lean SED and obese SED rats compared to their respective AL groups. G+M oxidation was decreased by 45% in lean SED and 30% in obese SED compared to their respective AL groups. No change in the capacity to oxidize PC+M was observed after loss of ovarian function when comparing SED to AL rats. In contrast, exercise resulted in an amelioration of the loss of mitochondrial oxidative capacity in lean rats. Following exercise, an increase of 10% in P+M, 25% in P+PC+M and 40% in G+M respiratory capacity was observed in lean EX compared to lean SED. Exercise was also observed to enhance the mitochondrial oxidative capacity of PC+M in lean EX by 20% compared to lean SED. In contrast to Lean rats, exercise did not counter the decline in mitochondrial capacity in obese rats. In fact, exercise seemed to exacerbate the decline in mitochondrial capacity, and the oxidation of P+PC+M was further decreased by 25%, as was PC+M (35%) in obese EX compared to obese SED. Similarly, oxidation of G+M was reduced by 10% in obese EX compared to obese SED. Citrate synthase and 3‐hyroxyacyl‐CoA dehydrogenase activities were evaluated to determine if there were limitations in either Krebs's cycle and/or β‐oxidation. Caloric restriction and exercise did not appear to impact either citrate synthase activity or 3‐hydroxyacyl‐CoA dehydrogenase activity. Additional studies are ongoing to determine to if these differences in mitochondrial capacities are magnified with respect to whole muscle capacities and/or capacities of the electron transport system. Support or Funding Information P50 HD073063, P30DK48520