Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi-centre factorial randomized trial

Abstract

Background: Physical activity and metformin pharmacotherapy are associated with improved clinical outcomes in breast and colorectal cancer survivors. Myokines are cytokines secreted from skeletal muscle that may mediate these associations.

Methods: This hypothesis-generating analysis used biospecimens collected from a multi-centre 2 × 2 factorial randomized design of 116 patients with stage I-III breast and colorectal cancer who were randomized to 12 weeks of (1) aerobic exercise (moderate intensity titrated to 220 min/week); (2) metformin (850 mg daily for 2 weeks and then titrated to 850 mg twice per day); (3) aerobic exercise and metformin; or (4) control. Fourteen myokines were quantified using a multiplex panel. Myokine concentrations were log-transformed, and main effects analyses were conducted using linear mixed-effects regression models. The type I error rate was controlled with the Holm sequential testing procedure.

Results: Randomization to exercise increased leukaemia inhibitory factor (1.26 pg/mL, 95% confidence interval [CI]: 0.69, 1.84; adjusted P = 0.001) and interleukin-15 (2.23 pg/mL, 95% CI: 0.87, 3.60; adjusted P = 0.013) compared with randomization to no exercise. Randomization to metformin decreased apelin (-2.69 pg/mL, 95% CI: -4.31, -1.07; adjusted P = 0.014) and interleukin-15 (-1.74 pg/mL, 95% CI: -2.79, -0.69; adjusted P = 0.013) compared with randomization to no metformin. Metformin decreased myostatin, irisin, oncostatin M, fibroblast growth factor 21 and osteocrin; however, these changes were not statistically significant after correction for multiple comparisons.

Conclusions: This pilot study demonstrates that randomization to exercise and metformin elicit unique effects on myokine concentrations in cancer patients. This hypothesis-generating observation warrants further basic, translational and clinical investigation and replication.

Keywords: biomarkers; diabetes; muscle; physical activity; recurrence; survival.

Figure 1

Mean myokine concentrations by exercise and metformin factorial groups. All myokines are in picograms per millilitre except osteonectin (nanograms per millilitre). Models adjusted for the baseline value of the dependent variable, body mass index (<30 vs. ≥30 kg/m²), gender (male vs. female), cancer site (colorectal vs. breast) and study centre (Dana‐Farber Cancer Institute vs. Duke University vs. Yale University). Factorial treatment group contrasts exercise (exercise group and exercise + metformin group) versus no exercise (metformin group and control group) and metformin (metformin group + metformin group and exercise group) versus no metformin (exercise group and control group). Nominal P values (unadjusted for multiple comparisons) are presented; see the text for adjusted P values. BDNF, brain‐derived neurotrophic factor; CI, confidence interval; FABP3, fatty acid binding protein 3; FGF‐21, fibroblast growth factor 21; FSTL‐1, follistatin‐related protein 1; IL‐6, interleukin‐6; IL‐15, interleukin‐15; LIF, leukaemia inhibitory factor.