Key result
DARS2 knockout selectively triggers mitochondrial remodeling and impaired autophagy in cardiac but not skeletal muscle.
Why the study?
Mitochondrial translation defects cause cardioskeletal myopathies, but how mitochondrial biogenesis and autophagic turnover diverge between striated muscles in vivo remains unclear.
This study reveals pronounced tissue divergence in mitochondrial remodeling in DARS2-related cardioskeletal myopathy and highlights the need for caution when interpreting colchicine-based autophagy flux assays in heart versus skeletal muscle.
Muscle-specific mitochondrial differences in DARS2 models warrant caution extrapolating to patients; leaves open mechanisms in human cardioskeletal myopathies.
Objective: Mitochondrial translation defects are a major cause of cardioskeletal myopathies, yet how mitochondrial biogenesis and autophagic turnover diverge between striated muscles in vivo remains unclear.Material and Methods: Using a heart- and skeletal muscle–specific mitochondrial aspartyl-tRNA synthetase (DARS2) knockout mouse model, mitochondrial protein markers (TOM20, VDAC) and biogenesis-associated transcripts (Tfam, Pgc-1α) were compared between the heart and quadriceps, and autophagy markers (LC3B-I/II and P62/SQSTM1) were assessed at baseline and following colchicine administration.Results: Knockout hearts displayed strong biogenesis-associated remodeling; in contrast, quadriceps displayed no induction of these markers. Steady-state autophagy markers in knockout hearts demonstrated reduced LC3B-II (and LC3B-II/I ratio) alongside marked P62 accumulation, which is consistent with impaired autophagic degradation/cargo clearance. Notably, colchicine did not elicit the expected LC3B-II accumulation in the heart, complicating straightforward flux interpretation in the cardiomyopathic context. In the quadriceps, colchicine robustly increased LC3B-II levels and the LC3B-II/LC3B-I ratio in both control and knockout muscles, indicating measurable autophagic response and supporting the technical feasibility of colchicine-based flux assays in this tissue.Conclusion: Together, these findings reveal pronounced tissue divergence in mitochondrial remodeling in DARS2-related cardioskeletal myopathy and underscore caution when interpreting colchicine-based autophagy flux assays in heart versus skeletal muscle.
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Şükrü Anıl Doğan (2026) studied Cardioskeletal myopathy. DARS2 knockout vs. Control was evaluated on Mitochondrial protein markers, biogenesis-associated transcripts, and autophagy markers. DARS2 knockout hearts displayed strong biogenesis-associated remodeling and impaired autophagic degradation, whereas quadriceps showed no induction of these markers.
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