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.
Highlights
Skeletal muscles, characterized by high metabolic activity [1] and constantly exposed to mechanical and oxidative stress, are susceptible to the formation of dysfunctional organelles and protein aggregates [2]
Expression of Hmox1 was not detectable, and it did not differ between 6-week-old wild-type (WT) and mdx animals (Figure 1A)
Duchenne muscular dystrophy (DMD), a disease resulting in progressive muscle weakness is caused by a mutation in the Dmd gene leading to the loss of dystrophin protein [23]
Summary
Skeletal muscles, characterized by high metabolic activity [1] and constantly exposed to mechanical and oxidative stress, are susceptible to the formation of dysfunctional organelles and protein aggregates [2]. Whether in response to the stressor cells decide to undergo apoptosis or autophagy, is strictly dependent on the nature of the stimulus and the balance between inhibitory and activating signals [3,4]. The sustained excessive level of autophagy flux degrades a large number of vital molecules and organelles, while not sufficient autophagic machinery causes protein inclusions and accumulation of damaged organelles [1,5]. A growing number of studies indicate dysregulation of autophagic flux in myoblasts as a hallmark of numerous muscular diseases, including muscular dystrophies [8].
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