Muscle Fiber Atrophy and Regeneration Coexist in Collagen VI-Deficient Human Muscle: Role of Calpain-3 and Nuclear Factor-κB Signaling

Abstract

Ullrich congenital muscular dystrophy (UCMD) is a common form of muscular dystrophy associated with defects in collagen VI. It is characterized by loss of individual muscle fibers and muscle mass and proliferation of connective and adipose tissues. We sought to investigate the mechanisms by which collagen VI regulates muscle cell survival, size, and regeneration and, in particular, the potential role of the ubiquitin-proteasome and calpain-proteolytic systems. We studied muscle biopsies of UCMD (n = 6), other myopathy (n = 12), and control patients (n = 10) and found reduced expression of atrogin-1, MURF1, and calpain-3 mRNAs in UCMD cases. Downregulation of calpain-3 was associated with changes in the nuclear immunolocalization of nuclear factor-κB. We also observed increased expression versus controls of regeneration markers at the protein and RNA levels. Satellite cell numbers did not differ in collagen VI-deficient muscle versus normal nonregenerating muscle, indicating that collagen VI does not play a key role in the maintenance of the satellite cell pool. Our results indicate that alterations in calpain-3 and nuclear factor-κB signaling pathways may contribute to muscle mass loss in UCMD muscle, whereas atrogin-1 and MURF1 are not likely to play a major role.

Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)

“…These findings therefore link a defect of the ECM to mitochondrial dysfunction followed by apoptosis that is preventable by inactivation of cyclophilin D by using cyclosporine A, its derivative Debio025 or genetic inactivation of cyclophilin D 51–53. However, there are contradictory reports in which researchers did not find evidence of myofiber apoptosis in biopsied muscles from UCMD patients or Col6a3 mutant mice muscles,54 55 suggesting that muscle cell death by apoptosis is not a universal phenomenon in all patients and collagen VI-deficient mice.…”

Calpain-14 and its association with eosinophilic esophagitis

“…16 Deficiency in CAPN3 also increases oxidative stress in the mitochondria because of accumulation of mitochondrial proteins involved in β-oxidation of fatty acids, 17 resulting in decreased nuclear localization of nuclear factor κB. Attenuated nuclear factor κB signaling leads to increased susceptibility to myocyte apoptosis, 18–21 production of eosinophil chemoattractants, 22 and eosinophil accumulation and activation, 13 as seen in patients with LGMD2A. The inflammatory component of LMGD2A is thought to be mediated by the eosinophil-derived secretory granule proteins, such as eosinophil cationic protein 23 and major basic protein.…”

A Comprehensive View of the Structural and Functional Alterations of Extracellular Matrix by Snake Venom Metalloproteinases (SVMPs): Novel Perspectives on the Pathophysiology of Envenoming

“…SVMP-induced hydrolysis of type VI collagen, and the consequent weakening of the mechanical stability of muscle BM, together with PLA 2 -induced plasma membrane perturbation, may be an example of toxin-toxin synergism to give rise to lesions to the periphery of muscle fibers, leading to myonecrosis. Likewise, by affecting the stability of muscle cell BM, type VI collagen hydrolysis might hamper the process of skeletal muscle regeneration, which depends on the integrity of muscle BM [85,86]. The observation that fragments of type VI collagen are more abundant at early time intervals in exudates from mice injected with B. asper venom suggests that such degradation is due to the action of SVMPs [41].…”