Dataset Information

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.

ABSTRACT:

Background

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by decreased expression of frataxin, a protein involved in many cellular metabolic processes, including mitochondrial oxidative phosphorylation (OXPHOS). Our objective was to assess skeletal muscle oxidative metabolism in vivo in adults with FRDA as compared to adults without FRDA using chemical exchange saturation transfer (CrCEST) MRI, which measures free creatine (Cr) over time following an in-magnet plantar flexion exercise.

Methods

Participants included adults with FRDA (n = 11) and healthy adults (n = 25). All underwent 3-Tesla CrCEST MRI of the calf before and after in-scanner plantar flexion exercise. Participants also underwent whole-body dual-energy X-ray absorptiometry (DXA) scans to measure body composition and completed questionnaires to assess physical activity.

Results

We found prolonged post-exercise exponential decline in CrCEST (τCr) in the lateral gastrocnemius (LG, 274 s vs. 138 s, p = 0.01) in adults with FRDA (vs. healthy adults), likely reflecting decreased OXPHOS capacity. Adults with FRDA (vs. healthy adults) also engaged different muscle groups during exercise, as indicated by muscle group-specific changes in creatine with exercise (∆CrCEST), possibly reflecting decreased coordination. Across all participants, increased adiposity and decreased usual physical activity were associated with smaller ∆CrCEST.

Conclusion

In FRDA, CrCEST MRI may be a useful biomarker of muscle-group-specific decline in OXPHOS capacity that can be leveraged to track within-participant changes over time. Appropriate participant selection and further optimization of the exercise stimulus will enhance the utility of this technique.

SUBMITTER: Schur GM

PROVIDER: S-EPMC9010488 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.

Schur Gayatri Maria GM Dunn Julia J Nguyen Sara S Dedio Anna A Wade Kristin K Tamaroff Jaclyn J Mitta Nithya N Wilson Neil N Reddy Ravinder R Lynch David R DR McCormack Shana E SE

Journal of neurology 20211015 5

<h4>Background</h4>Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by decreased expression of frataxin, a protein involved in many cellular metabolic processes, including mitochondrial oxidative phosphorylation (OXPHOS). Our objective was to assess skeletal muscle oxidative metabolism in vivo in adults with FRDA as compared to adults without FRDA using chemical exchange saturation transfer (CrCEST) MRI, which measures free creatine (Cr) over time following an in-magnet plantar f ...[more]

PMID: 34652504

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Project description:Abstract Background: Friedreich’s Ataxia (FA) is a neurodegenerative disease caused by disruptions in the gene encoding frataxin, a protein involved in formation of the iron-sulfur clusters needed for mitochondrial oxidative phosphorylation (OXPHOS). FA confers an increased risk for diabetes mellitus, but the mechanisms underlying this propensity are not well understood. Design: Cross-sectional study (clinicaltrials.gov: NCT02920671) Methods: Participants were non-diabetic individuals with FA (ages 18y-<65y) and healthy controls with a similar distribution of age, sex, BMI, and ancestry. OXPHOS capacity of calf muscle was assessed using a non-invasive, exercise-based MRI technique, creatine chemical exchange saturation transfer (CrCEST); results for lateral gastrocnemius (LG), the most consistently exercised muscle, are shown. After an overnight fast, a stable isotope tracer-enhanced oral glucose tolerance test was done. Body composition was assessed using dual energy x-ray absorptiometry. Linear regression analyses of the entire sample tested the association between outcomes and covariates (results are shown as standardized coefficient β). Results: This interim analysis has n=34 participants (11 FA, 23 control). Participants with FA were 61% male, median age 27y (IQI, 23-39), median BMI 26.9 kg/m2 (IQI, 24.1-29.4), and median visceral fat mass 0.50 kg (IQI, 0.35-0.70). Controls were 61% male, median age 29y (IQI, 26-38), median BMI 24.6 kg/m2 (IQI, 21.7-28.5), and median visceral fat mass 0.45 kg (IQI, 0.27-0.64). Fasting glucose was higher in FA (91 vs. 82 mg/dL, p=0.006). Lactate was similar at baseline and increased after oral glucose in both, but remained higher after 180min in FA (at 210min, 1.13 vs. 0.88 mmol/L, p=0.01). Post-exercise CrCEST recovery time constant (τCr) was increased 2.2-fold in FA (p=0.02), consistent with decreased OXPHOS capacity. In univariate analyses, whole body insulin sensitivity (WBISI) was decreased in FA (β -1.14, p=0.003), decreased with longer τCr, (β -0.48, p=0.01), and decreased with higher visceral fat (β -0.55, p=0.004). In multivariate analyses, these associations were attenuated when FA diagnosis (β -0.85, p=0.06) and τCr (β -0.25, p=0.25) were included in the same model, but were persistent when FA diagnosis (β -0.93, p=0.008) and visceral fat (β -0.43, p=0.01) were included in the same model. In univariate analyses, lactate area under the curve (AUC) was nominally increased in FA (β 0.67, p=0.11), and significantly positively associated with longer τCr (β 0.51, p=0.008). Conclusions: Individuals with a genetic mitochondrial disorder conferring increased diabetes risk have decreased whole body insulin sensitivity that may be mediated by decreased skeletal muscle OXPHOS capacity. Studies in rare disorders may provide insights into the role of skeletal muscle metabolism in the pathogenesis of Type 2 diabetes. Funding: NIH/NIDDK Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Dataset Information

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.

Background

Methods

Results

Conclusion

Publications

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.

Similar Datasets

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