Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic de-repression of the double homeobox 4 (DUX4) gene, leading to asymmetric muscle weakness and atrophy that begins in the facial and scapular muscles and progresses to the lower limbs. This incurable condition can severely impa...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-11-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/13/11/1406 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846154569973760000 |
|---|---|
| author | Manuela Moriggi Lucia Ruggiero Enrica Torretta Dario Zoppi Beatrice Arosio Evelyn Ferri Alessandra Castegna Chiara Fiorillo Cecilia Gelfi Daniele Capitanio |
| author_facet | Manuela Moriggi Lucia Ruggiero Enrica Torretta Dario Zoppi Beatrice Arosio Evelyn Ferri Alessandra Castegna Chiara Fiorillo Cecilia Gelfi Daniele Capitanio |
| author_sort | Manuela Moriggi |
| collection | DOAJ |
| description | Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic de-repression of the double homeobox 4 (DUX4) gene, leading to asymmetric muscle weakness and atrophy that begins in the facial and scapular muscles and progresses to the lower limbs. This incurable condition can severely impair muscle function, ultimately resulting in a loss of ambulation. A thorough analysis of molecular factors associated with the varying degrees of muscle impairment in FSHD is still lacking. This study investigates the molecular mechanisms and biomarkers in the biceps brachii of FSHD patients, classified according to the FSHD clinical score, the A-B-C-D classification scheme, and global proteomic variation. Our findings reveal distinct metabolic signatures and compensatory responses in patients. In severe cases, we observe pronounced metabolic dysfunction, marked by dysregulated glycolysis, activation of the reductive pentose phosphate pathway (PPP), a shift toward a reductive TCA cycle, suppression of oxidative phosphorylation, and an overproduction of antioxidants that is not matched by an increase in the redox cofactors needed for their function. This imbalance culminates in reductive stress, exacerbating muscle wasting and inflammation. In contrast, mild cases show metabolic adaptations that mitigate stress by activating polyols and the oxidative PPP, preserving partial energy flow through the oxidative TCA cycle, which supports mitochondrial function and energy balance. Furthermore, activation of the hexosamine biosynthetic pathway promotes autophagy, protecting muscle cells from apoptosis. In conclusion, our proteomic data indicate that specific metabolic alterations characterize both mild and severe FSHD patients. Molecules identified in mild cases may represent potential diagnostic and therapeutic targets for FSHD. |
| format | Article |
| id | doaj-art-cbb91547f81b4a15bafa83ebc259cbb4 |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-cbb91547f81b4a15bafa83ebc259cbb42024-11-26T17:47:19ZengMDPI AGAntioxidants2076-39212024-11-011311140610.3390/antiox13111406Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle FunctionManuela Moriggi0Lucia Ruggiero1Enrica Torretta2Dario Zoppi3Beatrice Arosio4Evelyn Ferri5Alessandra Castegna6Chiara Fiorillo7Cecilia Gelfi8Daniele Capitanio9Department of Biomedical Sciences for Health, University of Milan, Via Luigi Mangiagalli 31, 20133 Milan, ItalyDepartment of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, Via Sergio Pansini 5, 80131 Naples, ItalyLaboratory of Proteomics and Lipidomics, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20161 Milan, ItalyDepartment of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, Via Sergio Pansini 5, 80131 Naples, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, Via della Commenda 19, 20122 Milan, ItalyIRCCS Ca’ Granda Ospedale Maggiore Policlinico Foundation, Via Francesco Sforza 35, 20122 Milan, ItalyDepartment of Biosciences, Biotechnologies and Environment, University of Bari ALDO MORO, Via Orabona 4, 70125 Bari, ItalyChild Neuropsychiatric Unit, IRCCS Istituto Giannina Gaslini, DINOGMI-University of Genova, Via Gerolamo Gaslini 5, 16147 Genova, ItalyDepartment of Biomedical Sciences for Health, University of Milan, Via Luigi Mangiagalli 31, 20133 Milan, ItalyDepartment of Biomedical Sciences for Health, University of Milan, Via Luigi Mangiagalli 31, 20133 Milan, ItalyFacioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic de-repression of the double homeobox 4 (DUX4) gene, leading to asymmetric muscle weakness and atrophy that begins in the facial and scapular muscles and progresses to the lower limbs. This incurable condition can severely impair muscle function, ultimately resulting in a loss of ambulation. A thorough analysis of molecular factors associated with the varying degrees of muscle impairment in FSHD is still lacking. This study investigates the molecular mechanisms and biomarkers in the biceps brachii of FSHD patients, classified according to the FSHD clinical score, the A-B-C-D classification scheme, and global proteomic variation. Our findings reveal distinct metabolic signatures and compensatory responses in patients. In severe cases, we observe pronounced metabolic dysfunction, marked by dysregulated glycolysis, activation of the reductive pentose phosphate pathway (PPP), a shift toward a reductive TCA cycle, suppression of oxidative phosphorylation, and an overproduction of antioxidants that is not matched by an increase in the redox cofactors needed for their function. This imbalance culminates in reductive stress, exacerbating muscle wasting and inflammation. In contrast, mild cases show metabolic adaptations that mitigate stress by activating polyols and the oxidative PPP, preserving partial energy flow through the oxidative TCA cycle, which supports mitochondrial function and energy balance. Furthermore, activation of the hexosamine biosynthetic pathway promotes autophagy, protecting muscle cells from apoptosis. In conclusion, our proteomic data indicate that specific metabolic alterations characterize both mild and severe FSHD patients. Molecules identified in mild cases may represent potential diagnostic and therapeutic targets for FSHD.https://www.mdpi.com/2076-3921/13/11/1406facioscapulohumeral muscular dystrophyhexosamine biosynthetic pathwaymetabolic rewiringproteomicsredox cofactors |
| spellingShingle | Manuela Moriggi Lucia Ruggiero Enrica Torretta Dario Zoppi Beatrice Arosio Evelyn Ferri Alessandra Castegna Chiara Fiorillo Cecilia Gelfi Daniele Capitanio Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function Antioxidants facioscapulohumeral muscular dystrophy hexosamine biosynthetic pathway metabolic rewiring proteomics redox cofactors |
| title | Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function |
| title_full | Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function |
| title_fullStr | Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function |
| title_full_unstemmed | Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function |
| title_short | Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function |
| title_sort | muscle proteome analysis of facioscapulohumeral dystrophy patients reveals a metabolic rewiring promoting oxidative reductive stress contributing to the loss of muscle function |
| topic | facioscapulohumeral muscular dystrophy hexosamine biosynthetic pathway metabolic rewiring proteomics redox cofactors |
| url | https://www.mdpi.com/2076-3921/13/11/1406 |
| work_keys_str_mv | AT manuelamoriggi muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT luciaruggiero muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT enricatorretta muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT dariozoppi muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT beatricearosio muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT evelynferri muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT alessandracastegna muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT chiarafiorillo muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT ceciliagelfi muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction AT danielecapitanio muscleproteomeanalysisoffacioscapulohumeraldystrophypatientsrevealsametabolicrewiringpromotingoxidativereductivestresscontributingtothelossofmusclefunction |