Dysregulated Autophagy and Mitophagy in a Mouse Model of Duchenne Muscular Dystrophy Remain Unchanged Following Heme Oxygenase-1 Knockout

Abstract

Dysregulation of autophagy may contribute to the progression of various muscle diseases, including Duchenne muscular dystrophy (DMD). Heme oxygenase-1 (HO-1, encoded by Hmox1), a heme-degrading enzyme, may alleviate symptoms of DMD, inter alia, through anti-inflammatory properties. In the present study, we determined the role of HO-1 in the regulation of autophagy and mitophagy in mdx animals, a commonly used mouse model of the disease. In the gastrocnemius of 6-week-old DMD mice, the mRNA level of mitophagy markers: Bnip3 and Pink1, as well as autophagy regulators, e.g., Becn1, Map1lc3b, Sqstm1, and Atg7, was decreased. In the dystrophic diaphragm, changes in the latter were less prominent. In older, 12-week-old dystrophic mice, diminished expressions of Pink1 and Sqstm1 with upregulation of Atg5, Atg7, and Lamp1 was depicted. Interestingly, we demonstrated higher protein levels of autophagy regulator, LC3, in dystrophic muscles. Although the lack of Hmox1 in mdx mice influenced blood cell count and the abundance of profibrotic proteins, no striking differences in mRNA and protein levels of autophagy and mitophagy markers were found. In conclusion, we demonstrated complex, tissue, and age-dependent dysregulation of mitophagic and autophagic markers in DMD mice, which are not affected by the additional lack of Hmox1.

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

“…P62 is enhanced when autophagy is inhibited. It is interesting that our data showed a higher LC3-II:LC3-I and P62 in mdx mice, which was consistent with previous studies but lack of explanation (Supplemental Figures 2(f) and 2(g) ) [ 2 , 34 ]. Some researchers have pointed that though LC3 is an indispensable structure of autophagosome and a typically monitored autophagy-related protein, the preinitiation and degradation processes of autophagy do not rely on it [ 33 , 35 ].…”

NRF2 Regulates Viability, Proliferation, Resistance to Oxidative Stress, and Differentiation of Murine Myoblasts and Muscle Satellite Cells

“…The balance between mitophagy and mitochondrial biogenesis in the hypoxic stress response and control of the ROS level may be crucial for cell differentiation. Although we demonstrated that the lack of Hmox1 does not affect autophagy and mitophagy markers in dystrophic muscles [ 58 ], it does not exclude the possible role of NRF2 in hypoxia-regulated mSC differentiation. It could also be hypothesized that the observed changes in mSC differentiation may result from hypoxia-induced metabolic alterations.…”

Hydrogen sulfide as a therapeutic option for the treatment of Duchenne muscular dystrophy and other muscle-related diseases

“…Under dystrophic conditions, the gene expression of many proteins that participate in the autophagy process is dysregulated. We have found a decrease in the mRNA level of beclin-1 ( Becn1 ), autophagy-related genes 5 and 7 ( Atg5 , Atg7) , and lysosomal-associated membrane protein 1 ( Lamp1 ) in muscles from mdx mice [ 42 ]. The conversion of the soluble form of the microtubule-associated protein 1 light chain 3 (LC3-I) to lipid-bound LC3-II contributes to the formation of an autophagosome and is necessary, but not sufficient, to trigger cell autophagy [ 43 ].…”

“…Furthermore, defective mitochondria-specific autophagy, mitophagy was found in dystrophic muscles. The mechanism may involve dysregulation of the PINK1 (PTEN-induced kinase-1)/PARKIN (Parkinson juvenile disease protein-2) pathway [42,46]. The decrease in critical mitophagy-related factors, such as PINK1, PARK2, and BNIP3, has been demonstrated in dystrophic patients and various animal models of DMD (mice and worms) [42,47].…”

“…The mechanism may involve dysregulation of the PINK1 (PTEN-induced kinase-1)/PARKIN (Parkinson juvenile disease protein-2) pathway [42,46]. The decrease in critical mitophagy-related factors, such as PINK1, PARK2, and BNIP3, has been demonstrated in dystrophic patients and various animal models of DMD (mice and worms) [42,47]. On the other hand, the use of the mitophagy activator urolithin A alleviated the symptoms of DMD [47].…”