Our study was the first one to analyze the possibility of MMPs be involved in the pathogenesis of MFM. Interestingly, the results showed that MMP-2 and 9 are expressed in different compartments of skeletal muscle while in control muscles they were not demonstrated (Fig. 1).
We believe that both MMPs may participate actively in the pathological cascade leading to muscle membrane injury. MMP-9 comes from extracellular space into intracellular space and MMP-2 comes from intracellular space into extracellular space (Figs. 1, 2a). According to previous reports, MMP-2 is demonstrated in several subcellular compartments, including the thin and thick myofilaments, close to the Z disks of the cardiac sarcomere, the cytoskeleton, nuclei, mitochondria, and caveolae [4, 12]. Several intracellular processes are related to MMP-2 as cleaving specific proteins inside of myocytes thereafter reducing contractile function [4].
Particularly, MMP-2 presented significant expression (+) in the PN compartment (p < 0.001) in relation to MMP-9. By contrast, MMP-9 expression (+) was predominantly in the SS compartment demonstrating a possible influence of this gelatinase in ECM. In relation to IC compartment, our results were intriguing: both MMPs were expressed (+) in different regions of sarcoplasm. The same protein aggregate was expressed (+) by MMP-9 but not by MMP-2, and vice-versa in the same section (Fig. 2b).
So, there would be another component of cell signaling that could be part of the protein aggregate deposit and MMPs expressed would be just an epiphenomenon? Or why not, those MMPS expressed (PN, IC and SS) could not be protection factor to muscle fiber?
The mutations of known genes responsible for MFM will lead to an absence or dysfunction of coded proteins, causing mechanical instability of the sarcomere and, consequently, injury to the subcellular fiber compartments (ECM, sarcolemma, sarcoplasm, nucleus, and endoplasmic reticulum). The mechanical stress due to this instability would lead to MMP-2 upregulation with consequent destruction of the sarcomere, causing accumulation of proteins in the sarcoplasm (aggregates).