ABSTRACT

The increased energy required for acute moderate exercise by skeletal muscle (SkM) is derived equally from enhanced fatty acid (FA) oxidation and glucose oxidation. Availability of FA also influences contracting SkM metabolic responses. Whole body glucose turnover and SkM glucose metabolic responses were determined in paired dog studies during 1) a 30-min moderate exercise (maximal oxygen consumption of ∼60%) test vs. a 60-min low-dose 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) infusion, 2) a 150-min AICAR infusion vs. modest elevation of FA induced by a 150-min combined intralipid-heparin (IL/hep) infusion, and 3) an acute exercise test performed with vs. without IL/hep. The exercise responses differed from those observed with AICAR: plasma FA and glycerol rose sharply with exercise, whereas FA fell and glycerol was unchanged with AICAR; glucose turnover and glycolytic flux doubled with exercise but rose only by 50% with AICAR; SkM glucose-6-phosphate rose and glycogen content decreased with exercise, whereas no changes occurred with AICAR. The metabolic responses to AICAR vs. IL/hep differed: glycolytic flux was stimulated by AICAR but suppressed by IL/hep, and no changes in glucose turnover occurred with IL/hep. Glucose turnover responses to exercise were similar in the IL/hep and non-IL/hep, but SkM lactate and glycogen concentrations rose with IL/hep vs. that shown with exercise alone. In conclusion, the metabolic responses to acute exercise are not mimicked by a single dose of AICAR or altered by short-term enhancement of fatty acid supply.

Exercise vs. AICAR Infusion

With 30 min of moderate exercise, plasma glucose, insulin [4.1 ± 1.0 (before) vs. 3.0 ± 0.5 mU/l (after)], and glucagon [75 ± 17 (before) vs. 93 ± 21 ng/l (after); P = not significant (NS)] were unchanged; however, plasma FFA, lactate, and glycerol all rose significantly (P > 0.01) (Fig. 1). In contrast, with the 60-min AICAR infusion, plasma glucose fell (P = 0.05), insulin and glucagon were unchanged [insulin = 4.7 ± 0.5 (before) vs. 6.1 ± 0.8 mU/l (after), P = NS; glucagon = 53 ± 11 (before) vs. 68 ± 11 ng/l (after), P = NS], plasma FFA decreased significantly (P < 0.01), with no change in glycerol, and lactate rose sharply (P < 0.01) (Fig. 1). Thus the incremental responses of FFA and glycerol to exercise and AICAR were significantly different and in the opposite directions (Fig. 1). There was a greater than twofold increase (P < 0.02–0.01) in HGP, Rd, MCRg, and GFexog after the 30-min moderate exercise test (Fig. 2). In contrast, although these parameters also increased after the 60-min AICAR infusion (P < 0.02), the responses were considerably less (∼30–40%) and significantly (P < 0.01) smaller for the AICAR than for the exercise responses (Fig. 2). The metabolic responses to AICAR at 150 min were similar to those obtained at 60 min, with only a minor attenuation of MCRg by 150 min. SkM substrate concentrations of intracellular glucose and lactate did not change with exercise alone, whereas G6P significantly increased (change of 1.0 ± 0.3 mmol/l; P = 0.05) and glycogen decreased (change of –35 ± 36 mmol/kg dry wt; P = 0.06). In contrast, during AICAR infusion, a decrease in intracellular SkM glucose (change of –0.20 ± 0.0.9 mmol/l; P = 0.06) was noted, but no significant changes occurred in G6P, lactate, or glycogen. However, the absolute decrease of the glycogen concentration was significantly different for exercise compared with that for AICAR (change of –35 ± 36 vs. 9 ± 36 mmol/kg dry wt; P = 0.06). There were no changes in AMPK-α1 and AMPK-α2 activities with exercise or AICAR infusion (data not shown), but ACCβ-pSer221 was elevated by ∼35% [from basal level of 1.05 ± 0.02 to 1.38 ± 0.15 (P ≤ 0.05) with exercise and to 1.32 ± 0.15 (arbitrary units) (P = 0.06) with AICAR].


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Fig. 1. Paired comparisons of absolute plasma substrate responses and incremental changes (Δ) after either 30-min moderate exercise [exer; ∼60% maximal oxygen consumption (O2max); open bars] or 60-min low-dose 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) infusion (hatched bars) in 6 dogs. A: plasma (P) glucose. B: plasma free fatty acid (FFA). C: lactate. D: glycerol. *P = 0.05; **P < 0.01 vs. the within-group basal state; ††P < 0.01 between groups.


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Fig. 2. Paired comparisons of absolute responses and incremental changes (Δ) of hepatic glucose production (HGP; A), metabolic clearance rate of glucose (MCRg; B), Rd (C), and glycolytic flux (GFexog; D) to 30-min moderate exercise (∼60% O2max) (open bars) or 60-min AICAR infusion (hatched bars) in 6 dogs. *P < 0.02; **P < 0.01 vs. the within-group basal state; ††P < 0.01 between groups.

IL/Hep Infusion vs. Saline and AICAR Infusions

The 150-min IL/hep infusion alone raised plasma FFA by ∼60% and glycerol by ∼80% (P < 0.05–0.01) (Table 1). This resulted in a small but significant fall in fasting glucose (P ≤ 0.05), with no changes in insulin or glucagon (Table 1). There were also no changes induced by the IL/hep infusion in HGP, Rd, and MCRg, but GFexog fell significantly (P < 0.05) by ∼20% (Table 1). The effects of increasing FA supply compared with the AICAR infusion at 150 min were different (Table 1). Plasma glucose did not change; however, in the IL/hep group, the change in plasma lactate was markedly reduced (P < 0.001) and, as expected, FFA and glycerol were raised, compared with the responses observed in the AICAR studies (P ≤ 0.05–0.01) (Table 1). The modest significant increments observed for HGP, Rd, MCRg, and GFexog with AICAR were not observed in the IL/hep studies (Table 1). There was no relationship between the changes in plasma glucagon and HGP with the combined AICAR and IL/hep groups (r = 0.40, P = 0.22). After the IL/hep infusion, there were no changes (Δ) in intramuscular substrates (Δglucose = –0.05 ± 0.27 mmol/l, ΔG6P = 0.7 ± 0.7 mmol/kg dry wt, Δlactate = 0.51 ± 0.50 mmol/l, Δglycogen = 15 ± 33 mmol/kg dry wt, and ΔACCβ-pSer221 = 0.03 ± 0.05 arbitrary units).

Table 1. Comparison of the absolute and incremental effects of 60-min and 150-min AICAR infusion and 150-min saline or IL/heparin infusion on plasma substrates and hormones, glucose turnover, and skeletal muscle substrates in 6 resting normal dogs

Exercise With or Without IL/Hep Infusion

The exercise-induced responses of plasma substrates in the presence or absence of excess FA supply were similar for plasma glucose, glycerol, lactate, insulin, and glucagon. No exercise-induced increments for plasma FA were observed in the IL/hep group, since the FFA levels were already raised preexercise above those seen postexercise for the non-IL/hep group (Fig. 3). On the background of the lipid-induced lower basal GFexog (Table 1), the glucose turnover responses to exercise were similar for the IL/hep and non-IL/hep groups for HGP, Rd, MCRg, and GFexog (Fig. 4). Only small responses in the SkM substrates with exercise performed with and without IL/hep infusion were noted [Δglucose = 0.3 ± 0.1 vs. 0.0 ± 0.2 mmol/l, ΔG6P = 0.8 ± 0.6 vs. 1.0 ± 0.3 mmol/l, Δlactate = 2.6 ± 1.1 vs. 0.0 ± 0.3 mmol/l (P = 0.07), Δglycogen = 30 ± 37 vs. –35 ± 36 mmol/kg dry wt (P = 0.09), and ΔACCβ-pSer221 = 0.29 ± 0.06 vs. 0.23 ± 0.15 arbitrary units, respectively].


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Fig. 3. Paired comparisons of absolute responses and incremental changes of plasma substrates to 30-min moderate exercise (∼60% O2max), either in the absence [open bars, with saline (Sal)] or presence (hatched bars) of intralipid-heparin (IL/hep) infusion in 6 dogs. A: plasma glucose. B: plasma FFA. C: plasma lactate. D: plasma glycerol. *P < 0.05; **P < 0.01 vs. the within-group basal state; †P ≤ 0.06 between groups.


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Fig. 4. Paired comparisons of absolute responses and incremental changes of HGP (A), MCRg (B), Rd (C), and GFexog (D) to moderate exercise (∼60% O2max), either in the absence (open bars) or presence (hatched bars) of IL/hep infusion in 6 dogs. **P < 0.01 vs. the within-group basal state; †P ≤ 0.05 vs. the corresponding basal study without IL/hep.

 

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