Caspase-12 ablation preserves muscle function in the mdx mouse

Abstract

Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin. Several downstream consequences of dystrophin deficiency are triggers of endoplasmic reticulum (ER) stress, including loss of calcium homeostasis, hypoxia and oxidative stress. During ER stress, misfolded proteins accumulate in the ER lumen and the unfolded protein response (UPR) is triggered, leading to adaptation or apoptosis. We hypothesized that ER stress is heightened in dystrophic muscles and contributes to the pathology of DMD. We observed increases in the ER stress markers BiP and cleaved caspase-4 in DMD patient biopsies, compared with controls, and an increase in multiple UPR pathways in muscles of the dystrophin-deficient mdx mouse. We then crossed mdx mice with mice null for caspase-12, the murine equivalent of human caspase-4, which are resistant to ER stress. We found that deleting caspase-12 preserved mdx muscle function, resulting in a 75% recovery of both specific force generation and resistance to eccentric contractions. The compensatory hypertrophy normally found in mdx muscles was normalized in the absence of caspase-12; this was found to be due to decreased fibre sizes, and not to a fibre type shift or a decrease in fibrosis. Fibre central nucleation was not significantly altered in the absence of caspase-12, but muscle fibre degeneration found in the mdx mouse was reduced almost to wild-type levels. In conclusion, we have identified heightened ER stress and abnormal UPR signalling as novel contributors to the dystrophic phenotype. Caspase-4 is therefore a potential therapeutic target for DMD.

V8 induces apoptosis and the endoplasmic reticulum stress response in human multiple myeloma RPMI 8226 cells via the PERK-eIF2α-ATF4 signaling pathway

“…Previous studies have demonstrated that activation of caspase-12 occurs prior to the activation of executioner caspase-3 in the apoptosis of various cells associated with ER-stress (17,18,27). Consistent with the results of previous studies (11), the protein level of cleaved caspase-12 was increased following the same concentration of V8 stimulation in the present study.…”

Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress

“…Although a recent report showed increased GRP78/BiP and CHOP proteins in muscle of mdx mice and that ER stress-related caspase activity and apoptosis contributes to mdx pathology [15], this is the first study to provide insight into all three canonical pathways of UPR activation in conjunction with measures of oxidative stress and heat shock protein defense. Notably, the importance of ER stress to the pathology of mdx mice is consistent with other dystrophy studies reporting ER stress in sporadic inclusion body myositis (s-IBM) [41] and tibial muscular dystrophy (TMD) [42].…”

“…Indeed, a recent study showed that glucose regulated protein 78 (GRP78/BiP), which is a triggering factor for ER stress/UPR activation, was associated with ER-related apoptosis signaling in human DMD muscle and/or mdx mice [15]. A more thorough understanding of these processes in muscular dystrophy would provide further insight into the role these factors may play in mediating the disease pathology in order to develop new therapeutic tools.…”

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction

“…Caspase-12 has been detected only in mouse tissues, and caspase-4 may be its functional counterpart in humans. 33 The elucidation of mouse caspase-12 function may reveal the nature of caspase-4 in humans.…”