Mitochondrial‐Targeted Peptide SBT‐20 Improves Mitochondrial Bioenergetics In Duchenne Muscular Dystrophy In a Mitochondrial Creatine Kinase Dependent Manner
Bibliographic record
Abstract
RATIONALE Duchenne Muscular Dystrophy is a progressive muscle wasting disease in males resulting from mutations in the X‐linked gene dystrophin. The loss of dystrophin in the dystroglycan complex causes severe muscle pathology including cardiomyopathy which can lead to early death. While the cardiac dysfunction in mouse models of this disease has been well characterized, the precise signaling events contributing to this myopathy have yet to be determined. Given that this disease is associated with markers of oxidative stress, and that other models of cardiac dysfunction are associated with impaired mitochondrial oxidative phosphorylation (respiration) and elevated oxidant emission (H 2 O 2 ), we hypothesized that similar dysfunctions would exist in D2.B10‐DMD mdx /2J mice (DMD) that could be corrected with the mitochondrial targeted peptide SBT‐20. METHODS Left ventricular mitochondrial H 2 O 2 emission (spectrofluorometry; Amplex UltraRed fluorophore) and respiration (high‐resolution respirometry; Oroboros Oxygraph) were assessed in permeabilized muscle fibre bundles (PmFB) at 4 wk of age in DMD and DBA.2J wildtype (CONT), and again at 13–14 wk in DMD following daily subcutaneous injections of SBT‐20 (5mg/kg) or saline (0.9%) from 4 d for 12 weeks. H 2 O 2 emission was measured in the presence of physiological ADP (25μM) given ADP is a critical suppressor of H 2 O 2 emission during respiration that can be influenced by the phosphate‐shuttling activity of mitochondrial creatine kinase (mtCK). The contribution of mtCK was assessed by saturating [creatine] (Cr) in vitro. RESULTS AND INTERPRETATION At 4 wk, ADP‐suppression (25μM) of Complex I‐supported H 2 O 2 (5mM Pyruvate/2mM Malate) was impaired in DMD in the presence of Cr (+Cr; 36+/−4% of emission at 0μM ADP in DMD vs 12+/−1% of emission at 0μM ADP in CONT when expressed per O 2 consumed; p<0.01). This was also observed in the absence of Cr (−Cr; 36+/−4 vs 17+/−2% of 0μM ADP/O 2 consumed, p<0.01) suggesting H 2 O 2 emission is elevated in DMD independent of mtCK‐dependent phosphate shuttling. At this same [ADP], complex I‐supported respiration was lower in DMD vs CONT in both +Cr: (30.8+/−5.0 vs 54.2+/−10.2 pmol•s −1 •mg wet wt −1 , p<0.05) and ‐ Cr (35.0+/−1.2 vs 52.0+/−5.4 pmol•s −1 •mg wet wt −1 , p<0.01). After ~12 wk injections, SBT‐20‐treated DMD demonstrated greater ADP‐suppression of Complex I‐supported H 2 O 2 vs CONT in +Cr (12+/−1% vs 15+/−0 % of emission at 0μM ADP/O 2 consumed, p<0.01). However, there were no differences in ‐Cr (40+/−11 vs 42+/−13 % of 0μM ADP/O 2 consumed), suggesting SBT‐20 specifically improved mtCK‐dependent ADP suppression of H 2 O 2 emission. SBT‐20 did not change respiration in DMD vs CONT in +Cr (111.4 +/− 12.0 vs 82.1 +/− 11.2 pmol•s −1 •mg wet wt −1 , p=0.10) or –Cr condition (59.6 +/− 7.4 vs 65.3 +/− 6.8 pmol•s −1 •mg wet wt −1 ). Collectively, these findings demonstrate that SBT‐20 is an effective therapeutic approach for improving the ability of mtCK to mediate ADP‐suppression of H 2 O 2 in DMD heart. Support or Funding Information Funding was provided to C.G.R.P. by National Science and Engineering Research Council (#436138‐2013) with infrastructure supported by Canada Foundation for Innovation, Ontario Research Fund and the James H. Cummings Foundation. M.C.H. was supported by an NSERC CGS‐D scholarship.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".