Background

extracellular matrix (ECM) components are instrumental in maintaining homeostasis and muscle fiber functional integrity. Skeletal muscle hypertrophy is associated with ECM remodeling. Specifically, recent studies have reported the involvement of matrix metalloproteinases (MMPs) in muscle ECM remodeling. However, the functional role of MMPs in muscle hypertrophy remains largely unknown.

Methods

in this study, we examined the role of MMP-2 in skeletal muscle hypertrophy using a previously validated method where the plantaris muscle of mice were subjected to mechanical overload due to the surgical removal of synergist muscles (gastrocnemius and soleus).

Results

following two weeks of overload, we observed a significant increase in MMP-2 activity and up-regulation of ECM components and remodeling enzymes in the plantaris muscles of wild-type mice. However, MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to their wild-type littermates. Investigation of protein synthesis rate and Akt/mTOR signaling revealed no difference between wild-type and MMP-2 knockout mice, suggesting that a difference in hypertrophy was independent of protein synthesis.

Conclusion

taken together, our results suggest that MMP-2 is a key mediator of ECM remodeling in the setting of skeletal muscle hypertrophy.

Muscle extracellular matrix (ECM) plays an important role in maintaining muscular integrity and force transduction. However, the role of ECM in skeletal muscle atrophy remains unknown. In this study, we employed two clinically relevant mouse models of Achillotenotomy and hindlimb suspension to simulate Achilles tendon rupture and hindlimb disuse. The gastrocnemius was harvested following two weeks of treatment. We hypothesized that degradation of muscle ECM basement membrane lead to dysfunction of muscle contractility. Our results demonstrated a significant reduction of gastrocnemius single twitch force, isometric tetanic force, and contraction velocity following tendon rupture (p<0.001), but not disuse. Additionally, up-regulation of matrix metalloproteinase- 2 (MMP-2) was observed only after tendon rupture (p=0.00234). These findings suggest that ECM remodeling and basement membrane degradation due to MMP-2 may be responsible for declined muscle contractibility. Inhibiting ECM degradation enzymes may be a potential treatment strategy for skeletal muscle atrophy after tendon rupture.

Background

extracellular matrix (ECM) components are instrumental in maintaining homeostasis and muscle fiber functional integrity. Skeletal muscle hypertrophy is associated with ECM remodeling. Specifically, recent studies have reported the involvement of matrix metalloproteinases (MMPs) in muscle ECM remodeling. However, the functional role of MMPs in muscle hypertrophy remains largely unknown.

Methods

in this study, we examined the role of MMP-2 in skeletal muscle hypertrophy using a previously validated method where the plantaris muscle of mice were subjected to mechanical overload due to the surgical removal of synergist muscles (gastrocnemius and soleus).

Results

following two weeks of overload, we observed a significant increase in MMP-2 activity and up-regulation of ECM components and remodeling enzymes in the plantaris muscles of wild-type mice. However, MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to their wild-type littermates. Investigation of protein synthesis rate and Akt/mTOR signaling revealed no difference between wild-type and MMP-2 knockout mice, suggesting that a difference in hypertrophy was independent of protein synthesis.

Conclusion

taken together, our results suggest that MMP-2 is a key mediator of ECM remodeling in the setting of skeletal muscle hypertrophy.

Repair of peripheral nerve defects with current synthetic, tubular nerve conduits generally shows inferior recovery when compared with using nerve autografts, the current gold standard. We tested the ability of composite collagen and hyaluronan hydrogels, with and without the nerve growth factor (NGF), to stimulate neurite extension on a promising aligned, nanofiber poly-L-lactide-co-caprolactone (PLCL) scaffold. In vitro, the hydrogels significantly increased neurite extension from dorsal root ganglia explants. Consistent with these results, the addition of hydrogels as luminal fillers within aligned, nanofiber tubular PLCL conduits led to improved sensory function compared to autograft repair in a critical-size defect in the sciatic nerve in a rat model. Sensory recovery was assessed 3 and 12 weeks after repair using a withdrawal assay from thermal stimulation. The addition of hydrogel did not enhance recovery of motor function in the rat model. The NGF led to dose-dependent improvements in neurite out-growth in vitro, but did not have a significant effect in vivo. In summary, composite collagen/hyaluronan hydrogels enhanced sensory neurite outgrowth in vitro and sensory recovery in vivo. The use of such hydrogels as luminal fillers for tubular nerve conduits may therefore be useful in assisting restoration of protective sensation following peripheral nerve injury.