Gelatinases impart susceptibility to high-fat diet-induced obesity in mice

Abstract

Gelatinases play a role in adipose and muscle hypertrophy, and could be involved in tissue remodeling in response to high-fat diet (HFD) intake. This study tested potential roles of gelatinases (matrix metalloproteinses-2 and -9, MMP-2 and -9) in relationship to an antigrowth factor (myostatin, MSTN) known to be dysregulated in relation to HFD induced obesity (HFDIO) propensity. In vitro and ex vivo analyses demonstrated that MMP-9 increased mature MSTN levels, indicating a potential role of gelatinases in MSTN activation in vivo. HFD intake resulted in increased body weight and circulating blood glucose values in C57BL/6J and MMP-9 null mice, with no changes observed in SWR/J mice. HFD intake attenuated MMP-9 and MMP-2 mRNA levels in SWR/J mice while elevating MMP-2 levels in skeletal musclein C57BL/6J mice.In MMP-9 null mice, the effects of HFD intake were muted. Consistent with changes in mRNA levels, HFD intake increased MMP-9 activity in muscle tissue of C57BL/6J mice, demonstrating a strong relationship between HFDIO susceptibility and local MMP regulation. Overall, resistance to HFDIO appears to correspond to low MMP-9 and MSTN levels, suggesting a role of MMP-9 in MSTN activation in local tissue responses to HFD intake.

The emerging role of skeletal muscle extracellular matrix remodelling in obesity and exercise

“…After 6 weeks of high‐fat feeding (60% fat), they found that up‐regulation of mRNA levels and activity of MMP‐2 and MMP‐9 were characteristic of C57BL/6 mice. In contrast, none of these changes were seen in non‐susceptible mice . Similarly, in another study using 16 weeks of HFD feeding in mice, MMP‐9 plasma activity was also increased, despite decreased protein levels in skeletal muscle .…”

“…Similarly, in another study using 16 weeks of HFD feeding in mice, MMP‐9 plasma activity was also increased, despite decreased protein levels in skeletal muscle . MMP‐9 has been shown to be released in response to growth factors such as myostatin, thus promoting a turnover of ECM components in skeletal muscle . In contrast, Kang et al reported that despite increases in collagen III and IV protein content in gastrocnemius muscle of C57BL/6 mice after 14 to 20 weeks HFD (60% fat), MMP‐9 activity was decreased, while MMP‐2 showed no differences .…”

“…In the context of obesity and metabolic disease, mounting evidence is emerging that the skeletal muscle ECM is perturbed in obese and insulin‐resistant conditions . Compared with lean individuals, collagen abundance (total, I and III) is increased in vastus lateralis biopsies taken from obese insulin‐resistant subjects , and in diet‐induced obese mice, insulin resistance and muscle collagen (III and IV) deposition are rescued by pharmacological or genetic manipulation targeting the ECM .…”

“…Fibroblasts are shown in green. [Colour figure can be viewed at wileyonlinelibrary.com] Muscle extracellular matrix during obesity S. Martinez-Huenchullan et al 777 obesity reviews (7,8,10,(33)(34)(35). Compared with lean individuals, collagen abundance (total, I and III) is increased in vastus lateralis biopsies taken from obese insulin-resistant subjects (6), and in diet-induced obese mice, insulin resistance and muscle collagen (III and IV) deposition are rescued by pharmacological or genetic manipulation targeting the ECM (7,8,35).…”

Effective MSTN Gene Knockout by AdV-Delivered CRISPR/Cas9 in Postnatal Chick Leg Muscle

“…One was FMOD, which is not only a new regulator of MSTN during myoblast differentiation but can also circumvent the inhibitory effect of MSTN and trigger myoblast differentiation [39]. Another was MMP9, which plays a role in regulating MSTN and causes muscle hypertrophy when genetically manipulated [40,41]. In the present research, through GO enrichment analysis, many genes, such as, SCX, Pax3, VTN, EOMES, PAX5, MYC, NOX4, P2RY6, ITGA2, CCL5, PGR, SRC, P2RY6, TNFRSF25, TCF7, CXCL13, SFRP1 etc., were found to be involved in the skeletal muscle cell differentiation, positive regulation of smooth muscle cell migration, regulation of cell proliferation, and negative regulation of cell growth.…”