Mitochondrial stress responses in Duchenne muscular dystrophy: metabolic dysfunction or adaptive reprogramming?
Catherine A Bellissimo1, Madison C Garibotti1, Christopher G R Perry1
1School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
Abstract:
Mitochondrial stress may be a secondary contributor to muscle weakness in inherited muscular dystrophies. Duchenne muscular dystrophy has received the majority of attention, whereby most discoveries suggest mitochondrial ATP synthesis may be reduced. However, not all studies support this finding. Furthermore, some studies have reported increased mitochondrial reactive oxygen species and propensity for permeability transition pore formation as an inducer of apoptosis, although divergent findings have also been described. A closer examination of the literature suggests the degree and direction of mitochondrial stress responses may depend on the progression of the disease, the muscle type examined, the mouse model used with regard to preclinical research, the precise metabolic pathways in consideration, and in some cases, the in vitro technique used to assess a given mitochondrial bioenergetic function. One intent of this review is to provide careful considerations for future experimental designs to resolve the heterogeneous nature of mitochondrial stress during the progression of Duchenne muscular dystrophy. Such considerations have implications for other muscular dystrophies as well which are addressed briefly herein. A renewed perspective of the term "mitochondrial dysfunction" is presented whereby stress responses might be re-explored in future investigations as direct contributors to myopathy versus an adaptive "reprogramming" intended to maintain homeostasis in the face of disease stressors themselves. In so doing, the prospective development of mitochondrial enhancement therapies can be driven by advances in perspectives as much as experimental approaches when resolving the precise relationships between mitochondrial remodeling and muscle weakness in Duchenne and, indeed, other muscular dystrophies.
Insights
Mitochondrial stress in Duchenne muscular dystrophy shows varied responses, potentially adapting to disease rather than solely causing weakness. Future research needs careful design to understand these complex mitochondrial dynamics.
Area of Science:
- Biochemistry
- Cell Biology
- Neuromuscular Disorders
Background:
- Mitochondrial stress is implicated in muscle weakness in inherited muscular dystrophies, particularly Duchenne muscular dystrophy (DMD).
- Existing research presents conflicting findings regarding mitochondrial ATP synthesis, reactive oxygen species (ROS) production, and apoptosis propensity in DMD.
- The heterogeneity in findings may stem from disease progression stage, muscle type, animal models, metabolic pathways, and experimental techniques.
Purpose of the Study:
- To critically review the literature on mitochondrial stress responses in Duchenne muscular dystrophy (DMD).
- To propose considerations for future experimental designs to address the heterogeneous nature of mitochondrial stress in DMD.
- To offer a renewed perspective on "mitochondrial dysfunction" as potentially adaptive reprogramming versus direct pathology.
Main Methods:
- Comprehensive literature review and analysis of existing studies on mitochondrial function in muscular dystrophies.
- Examination of factors influencing mitochondrial stress responses, including disease stage, tissue type, and methodology.
- Synthesis of divergent findings to identify patterns and propose future research directions.
Main Results:
- Mitochondrial ATP synthesis, ROS levels, and apoptosis propensity show inconsistent results across studies in DMD.
- The observed mitochondrial stress responses are highly dependent on disease progression, muscle specificity, preclinical models, and experimental assays.
- A nuanced understanding of mitochondrial stress as a potential adaptive response or direct contributor to myopathy is emerging.
Conclusions:
- Future research on mitochondrial stress in DMD requires standardized and carefully considered experimental designs to resolve conflicting data.
- Re-evaluating mitochondrial stress responses as adaptive mechanisms could offer new therapeutic avenues.
- Understanding mitochondrial remodeling in DMD and other muscular dystrophies is crucial for developing effective mitochondrial enhancement therapies.
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