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Peer-reviewedCC BYJournal of Cachexia, Sarcopenia and Muscle

Quantitative Muscle MRI Fat Fraction as a Biomarker of Disease Severity in Mitochondrial Myopathies

  • Ana Bermejo‐Moriñigo1
  • Paloma Martín‐Jiménez2
  • Violeta González‐Méndez1
  • Laura Bermejo‐Guerrero2
  • Luz Edith Ochoa3
  • Cristina Martín‐Arriscado4
  • Andrea Alcalá‐Galiano1
  • Cristina Casado‐Pérez1
  • María Navarro‐Riquelme3
  • Rocío Garrido‐Moraga3
  • Adrián González Quintana3
  • Alberto Blázquez3
1 more authors
  • Cristina Domínguez‐González2
4 affiliations
  1. 1Radiology Department Hospital Universitario 12 de Octubre Madrid Spain
  2. 2Neuromuscular Diseases Unit, Neurology Department Hospital Universitario 12 de Octubre Madrid Spain
  3. 3Mitochondrial and Neuromuscular Research Group ‘12 de Octubre’ Instituto de Investigación Hospital Universitario 12 de Octubre (imas12) Madrid Spain
  4. 4Unidad de Investigación y Soporte Científico Instituto de Investigación Hospital Universitario 12 de Octubre (imas12) Madrid Spain
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Abstract

Background Quantitative muscle MRI is increasingly used to assess structural muscle damage in inherited myopathies, but its application in primary mitochondrial myopathies (PMM) has not been systematically evaluated in large cohorts. Because PMM are clinically and genetically heterogeneous, objective imaging biomarkers are needed to quantify skeletal‐muscle involvement and define meaningful subgroups. We assessed whether MRI‐derived proton density fat fraction (PDFF) captures genotype‐ and phenotype‐specific patterns of fatty replacement and reflects disease severity using motor function outcomes and circulating biomarkers. Methods We performed a cross‐sectional analysis of 49 adults with genetically confirmed PMM enrolled in a prospective natural history study. Participants underwent standardised lower‐limb MRI, including T1‐weighted sequences and mDIXON‐QUANT fat fraction imaging. Muscle involvement was assessed semi‐quantitatively with the modified Mercuri scale and quantitatively by PDFF measurement in selected pelvic girdle and thigh muscles. A total fat fraction score (FF sum) was calculated. PDFF was compared across genotypes and phenotypes and against MRC score, NSAA, 6‐min walk test, 100‐m run test, CK, serum creatinine, GDF15 and disease duration. Results Mean age at onset was 26.3 ± 15.1 years, mean age at MRI was 50.0 ± 12.3 years, and median disease duration was 23 years (IQR 15–31). Genetic diagnoses included mtDNA variants in 29 patients (59.1%; single large‐scale deletions, n = 19; point mutations, n = 10), nuclear variants in POLG (n = 8), TK2 (n = 8) and TWNK (n = 4). Phenotypes were exercise intolerance without overt weakness (n = 7), isolated progressive external ophthalmoplegia (PEO; n = 16), PEO‐plus (n = 16) and progressive myopathy (n = 8). Highest median PDFF values were observed in tensor fasciae latae (31%), gluteus maximus (30%), sartorius (25%) and gracilis (20%). FF sum correlated with MRC score (r = −0.567, p < 0.0001), NSAA (r = −0.731, p < 0.0001), 100‐m run test time (r = 0.629, p < 0.0001), 6‐min walk distance (r = −0.311, p = 0.0476) and serum creatinine (r = −0.715, p < 0.0001), but not with CK or GDF15. TK2 deficiency showed the highest fat replacement, particularly in gluteus maximus and gracilis (p < 0.001). Progressive myopathy showed greater fatty replacement than other phenotypes (p < 0.001), while exercise intolerance showed higher fat fraction than isolated PEO (p = 0.033). Conclusions Quantitative muscle MRI provides objective and clinically meaningful measures of muscle involvement in PMM. MRI‐derived fat fraction reflects disease severity, discriminates between genotypes and phenotypes, and detects subclinical muscle damage. These cross‐sectional findings support PDFF as a candidate imaging biomarker for patient stratification and disease characterisation; prospective longitudinal studies will be required to establish its sensitivity to change and its validity as an outcome measure for therapeutic trials.

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Cite

BibTeXRIS
BibTeX
@article{bermejomorinigo2026quantitative,
  title = {{Quantitative Muscle MRI Fat Fraction as a Biomarker of Disease Severity in Mitochondrial Myopathies}},
  author = {Ana Bermejo‐Moriñigo and Paloma Martín‐Jiménez and Violeta González‐Méndez and Laura Bermejo‐Guerrero and Luz Edith Ochoa and Cristina Martín‐Arriscado and Andrea Alcalá‐Galiano and Cristina Casado‐Pérez and María Navarro‐Riquelme and Rocío Garrido‐Moraga and Adrián González Quintana and Alberto Blázquez and Cristina Domínguez‐González},
  journal = {Journal of Cachexia, Sarcopenia and Muscle},
  year = {2026},
  month = oct,
  doi = {10.1002/jcsm.70380},
  url = {https://doi.org/10.1002/jcsm.70380},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Quantitative Muscle MRI Fat Fraction as a Biomarker of Disease Severity in Mitochondrial Myopathies
AU  - Ana Bermejo‐Moriñigo
AU  - Paloma Martín‐Jiménez
AU  - Violeta González‐Méndez
AU  - Laura Bermejo‐Guerrero
AU  - Luz Edith Ochoa
AU  - Cristina Martín‐Arriscado
AU  - Andrea Alcalá‐Galiano
AU  - Cristina Casado‐Pérez
AU  - María Navarro‐Riquelme
AU  - Rocío Garrido‐Moraga
AU  - Adrián González Quintana
AU  - Alberto Blázquez
AU  - Cristina Domínguez‐González
PY  - 2026
DA  - 2026/10/26
JO  - Journal of Cachexia, Sarcopenia and Muscle
DO  - 10.1002/jcsm.70380
UR  - https://doi.org/10.1002/jcsm.70380
AB  - Background Quantitative muscle MRI is increasingly used to assess structural muscle damage in inherited myopathies, but its application in primary mitochondrial myopathies (PMM) has not been systematically evaluated in large cohorts. Because PMM are clinically and genetically heterogeneous, objective imaging biomarkers are needed to quantify skeletal‐muscle involvement and define meaningful subgroups. We assessed whether MRI‐derived proton density fat fraction (PDFF) captures genotype‐ and phenotype‐specific patterns of fatty replacement and reflects disease severity using motor function outcomes and circulating biomarkers. Methods We performed a cross‐sectional analysis of 49 adults with genetically confirmed PMM enrolled in a prospective natural history study. Participants underwent standardised lower‐limb MRI, including T1‐weighted sequences and mDIXON‐QUANT fat fraction imaging. Muscle involvement was assessed semi‐quantitatively with the modified Mercuri scale and quantitatively by PDFF measurement in selected pelvic girdle and thigh muscles. A total fat fraction score (FF sum) was calculated. PDFF was compared across genotypes and phenotypes and against MRC score, NSAA, 6‐min walk test, 100‐m run test, CK, serum creatinine, GDF15 and disease duration. Results Mean age at onset was 26.3 ± 15.1 years, mean age at MRI was 50.0 ± 12.3 years, and median disease duration was 23 years (IQR 15–31). Genetic diagnoses included mtDNA variants in 29 patients (59.1%; single large‐scale deletions, n = 19; point mutations, n = 10), nuclear variants in POLG (n = 8), TK2 (n = 8) and TWNK (n = 4). Phenotypes were exercise intolerance without overt weakness (n = 7), isolated progressive external ophthalmoplegia (PEO; n = 16), PEO‐plus (n = 16) and progressive myopathy (n = 8). Highest median PDFF values were observed in tensor fasciae latae (31%), gluteus maximus (30%), sartorius (25%) and gracilis (20%). FF sum correlated with MRC score (r = −0.567, p < 0.0001), NSAA (r = −0.731, p < 0.0001), 100‐m run test time (r = 0.629, p < 0.0001), 6‐min walk distance (r = −0.311, p = 0.0476) and serum creatinine (r = −0.715, p < 0.0001), but not with CK or GDF15. TK2 deficiency showed the highest fat replacement, particularly in gluteus maximus and gracilis (p < 0.001). Progressive myopathy showed greater fatty replacement than other phenotypes (p < 0.001), while exercise intolerance showed higher fat fraction than isolated PEO (p = 0.033). Conclusions Quantitative muscle MRI provides objective and clinically meaningful measures of muscle involvement in PMM. MRI‐derived fat fraction reflects disease severity, discriminates between genotypes and phenotypes, and detects subclinical muscle damage. These cross‐sectional findings support PDFF as a candidate imaging biomarker for patient stratification and disease characterisation; prospective longitudinal studies will be required to establish its sensitivity to change and its validity as an outcome measure for therapeutic trials.
SN  - 2190-6009
SN  - 2190-5991
ER  -