Skeletal muscle extracellular matrix remodeling after short-term overfeeding in healthy humans

Skeletal muscle extracellular matrix (ECM) remodeling has been proposed as a feature of the pathogenic milieu associated with obesity and metabolic dysfunction. The aim of the current study was to examine the timeline of this response and determine whether 3 and 28days of overfeeding alters markers of ECM turnover.

Forty healthy individuals were overfed by 1250kcal/day for 28days. Hyperinsulinemic-euglycemic clamps and abdominal fat distribution were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28. mRNA expression (COL1a1, COL3a1, MMP2, MMP9, TIMP1, CD68, Integrin) was performed in 19 subjects that consented to having all biopsies performed and microarray analysis was performed in 8 participants at baseline and day 28.

In the whole cohort, body weight increased by 0.6±0.1 and 2.7±0.3kg at days 3 and 28 (both P<0.001), respectively. Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8±2.8 at baseline to 50.3±2.5μmol/min/kg FFM at day 28 of overfeeding (P=0.03). Muscle COL1 and COL3 and MMP2 mRNA levels were significantly higher 28days after overfeeding (all P<0.05), with no significant changes in MMP9, TIMP1, CD68 and integrin expression. Microarray based gene set tests revealed that pathways related to ECM receptor interaction, focal adhesion and adherens junction were differentially altered.

Skeletal muscle ECM remodeling occurs early in response to over-nutrition with as little as 3% body weight gain. Our findings contribute to the growing evidence linking muscle ECM remodeling and accumulation as another sequela of obesity-related insulin resistance.