TRIM72 Alleviates Muscle Inflammation in mdx Mice via Promoting Mitophagy-Mediated NLRP3 Inflammasome Inactivation

Abstract

Chronic muscle inflammation exacerbates the pathogenesis of Duchenne muscular dystrophy (DMD), which is characterized by progressive muscle degeneration and weakness. NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome plays a key role in the inflammatory process, and its abnormal activation leads to a variety of inflammatory or immune diseases. TRIM72 (MG53) is a protective myokine for tissue repair and regeneration. However, little is known about the potential impact of TRIM72 in the crosstalk between mitophagy and inflammatory process of DMD. Here, 10-week-old male mdx mice were injected intramuscularly with adeno-associated virus (AAV-TRIM72) to overexpress TRIM72 protein for 6 weeks. Then, skeletal muscle samples were collected, and relevant parameters were measured by histopathological analysis and molecular biology techniques. C2C12 cell line was transfected with lentivirus (LV-TRIM72) to overexpress or siRNA (si-TRIM72) to suppress the TRIM72 expression for the following experiment. Our data firstly showed that the TRIM72 expression was decreased in skeletal muscles of mdx mice. Then, we observed the increased NLRP3 inflammasome and impaired mitophagy in mdx mice compared with wild type mice. In mdx mice, administration of AAV-TRIM72 alleviated the accumulation of NLRP3 inflammasome and the consequent IL-18 and IL1β maturation by inducing autophagy, while this protective effect was reversed by chloroquine. Mitochondrial reactive oxygen species (mtROS), as a recognized activator for NLRP3 inflammasome, was attenuated by TRIM72 through the induction of mitophagy in C2C12 cells. Additionally, we proposed that the TRIM72 overexpression might promote mitophagy through both the early stage by PI3K-AKT pathway and the late stage by autolysosome fusion. In conclusion, the current study suggests that TRIM72 prevents DMD inflammation via decreasing NLRP3 inflammasomes and enhancing mitophagy. Collectively, our study provides insight into TRIM72 as a promising target for therapeutic intervention for DMD.

TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein

“…A previous study has indicated that TRIM72 attenuated LPS-induced neurotoxicity and neuroinflammation by inhibiting TLR4/NF-κB pathway both in vitro and in vivo [ 44 ]. A recent study has revealed that TRIM72 reduces muscle inflammation by promoting the inactivation of NLRP3 inflammasome [ 45 ]. Additionally, several studies have found a connection between TRIM72 and the influenza virus, demonstrating that TRIM72 protects mice from lethal influenza virus infection by suppressing interferon-β and inflammation [ 29 , 46 ].…”

TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein

“…A previous study has indicated that TRIM72 attenuated LPS-induced neurotoxicity and neuroinflammation by inhibiting TLR4/NF-kB pathway both in vitro and in vivo [39]. A recent study has revealed that TRIM72 reduces muscle inflammation by promoting the inactivation of NLRP3 inflammasome [40]. Additionally, several studies have found a connection between TRIM72 and the influenza virus, demonstrating that TRIM72 protects mice from lethal influenza virus infection by suppressing inflammation [41, 42].…”

Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy

“…Mitochondria structure is altered even before the onset of muscle fiber damage and metabolic defects, lowered mitochondrial potential, and promoting excessive mtROS production [52]. In both DMD patients and animal models (mice and worms), autophagy and mitophagy appear to be significantly compromised, leading to the accumulation of damaged mitochondria that could negatively impact the muscle [53][54][55][56]. Interestingly, the inhibition of autophagy is evident with the progression of the disease, concomitant with the fibrotic phase and the exhaustion of stem-cell-mediated regeneration.…”

“…Mitophagy is also impaired in DMD animal models, in mdx mice as well as dystrophic worms, and occurs in mature muscle fiber and muscle stem cells as well [55,64]. Mitophagy dysfunctions are associated with damage-associated molecular patterns (DAMPs) release, such as mtROS and mtDNA, which leads to activation of the NLRP3 inflammasome and promotes IL-1β and IL-18 secretion [54]. Accordingly, enhancing mitophagy by TRIM72 overexpression, a myokine with a protective role in tissue repair and regeneration, blunts the inflammasome increase and mitigates the inflammatory response, with positive effects in DMD [54].…”