A potent physiological method to magnify and sustain soleus oxidative metabolism improves glucose and lipid regulation

Abstract

Slow oxidative muscle, most notably the soleus, is inherently well equipped with the molecular machinery for regulating blood-borne substrates. However, the entire human musculature accounts for only ∼15% of the body's oxidative metabolism of glucose at the resting energy expenditure, despite being the body's largest lean tissue mass. We found the human soleus muscle could raise local oxidative metabolism to high levels for hours without fatigue, during a type of soleus-dominant activity while sitting, even in unfit volunteers. Muscle biopsies revealed there was minimal glycogen use. Magnifying the otherwise negligible local energy expenditure with isolated contractions improved systemic VLDL-triglyceride and glucose homeostasis by a large magnitude, e.g., 52% less postprandial glucose excursion (∼50 mg/dL less between ∼1 and 2 h) with 60% less hyperinsulinemia. Targeting a small oxidative muscle mass (∼1% body mass) with local contractile activity is a potent method for improving systemic metabolic regulation while prolonging the benefits of oxidative metabolism.

Keywords: Health sciences; Human metabolism; Physiology.

Hamilton, MT. et al. (2022) iScience. A potent physiological method to magnify and sustain soleus oxidative metabolism improves glucose and lipid regulation

Figure 1

Minimal contribution from soleus glycogen to the total energy for contractions (the activity energy expenditure) during prolonged local activity of the soleus with SPU contractions Individual results are shown with the mean ± SEM. N = 10 in Experiment I. The glycogen contribution was negligible at both 130 and 270 min and significantly less than the total energy demand for contractions at both time points (both p < 0.0001, mixed effects model followed by Tukey’s multiple comparison tests). See also Figures S7 and S8, and Table 1 for more details.

Figure 2

Whole-body and local oxidative metabolism during SPU contractions when sitting and during treadmill exercise (A) SPU contractions approximately doubled whole-body VO2 above the normal resting metabolic rate when sitting (p = 8 × 10⁻⁸, paired t test, N = 10). (B) The relative contribution of the medial gastrocnemius (MG), soleus (SOL), and lateral gastrocnemius (LG) to the estimated proportion of the recruited mass as determined with MRI and EMG. (C) The calculated VO2 per kg soleus muscle during SPU contractions as a mode of isolated plantarflexion was compared with the VO2 per kg of the whole lower limb musculature during walking at a moderate-intensity (p = 0.00001) and high-intensity treadmill exercise (p = 0.001). Statistics were determined with a mixed effects model followed by Tukey’s multiple comparison tests. Individual results of 10 untrained/unfit participants with an average VO2max of 30 mL/min/kg body weight are shown with the mean ± SEM. See also Figure S1.

Figure 3

Sustaining elevated muscle metabolism with soleus contractions is sufficient to cause improved glucose tolerance and reduced postprandial hyperinsulinemia, with up to a 52%–60% reduction in the blood glucose and insulin iAUC See Table 2 for complete results of the energetics for SPU1 (N = 15) and SPU2 (N = 10). Responses reveal a robust soleus muscle activity-dependent glucose (A) and insulin (B) lowering in each individual during a 3-h 75-g OGTT. Statistical summary (C and D) of the average iAUC responses from 0 to 180 min. Effect sizes are calculated by Cohen’s d test. SPU1 and SPU2 had effect sizes considered to be “huge” (>2.0) (Sawilowsky, 2009) for both glucose and insulin iAUC. (E) This index is the average of the glucose iAUC and the insulin iAUC for each individual, expressed relative to when sitting inactive (SED). Differences between conditions were determined by mixed effects models followed by Tukey’s multiple comparison tests. Mean ± SEM. The actual glucose concentration differences between conditions at each time point are in Table 3.

Figure 4

Recruitment during locally intense activation of a small mass dominated by the soleus consistently has the capability to raise whole-body carbohydrate oxidation above the rest of the body (A) The rate of carbohydrate oxidation after ingesting a glucose load was consistently increased during both levels of local contractile activity (see Table 2 for more results). The fasted condition was measured sitting at rest prior to the OGTT, and SED was the inactive control condition during the OGTT. SPU1 (N = 15) and SPU2 (N = 10). Differences between conditions were determined by mixed effects models followed by Tukey’s multiple comparison tests. (B) A model summarizing the influence of a small muscle mass on oxidative metabolism during the 75 g OGTT. Although contributing a negligible amount to systemic metabolism when not contracting, the energy demand of even a relatively small muscle mass has the potential to contribute meaningfully to carbohydrate metabolism when contracting with this single isolated SPU movement. This model is consistent with the findings that the total body skeletal muscle mass at rest accounts for ∼15% of the total systemic glucose oxidation in the postprandial period in nondiabetic controls with similar age and BMI as participants in the present study (Kelley et al., 1994). SPU contractions caused a 2.1- (SPU1) and 2.9-fold (SPU2) increase in the total body carbohydrate oxidation (Figure 4A). As shown in red bars in Figure 4B, the local contractile activity was sufficient to raise glucose oxidation above all inactive muscles and other body tissues combined.