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Peer-reviewedCC BY 4.0Biomolecules

Interferon-Associated Inflammatory Remodeling and Oxidative Metabolic Repression Define the Skeletal Muscle Transcriptomic Landscape of δ-Sarcoglycan Deficiency

  • Amairani Cancino-Bello1
  • Mauricio Hernández-Somilleda1
  • Erick Bahena-Culhuac1
  • Estela G. García-González2
  • Oscar Hernández-Hernández3
  • Ramón M. Coral-Vázquez4,5
  • J. Manuel Hernández-Hernández1,2
5 affiliations
  1. 1Laboratorio de Epigenética de la Regeneración Muscular, Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados (CINVESTAV-IPN), Mexico City 07360, Mexico
  2. 2Laboratorio de Epigenética de la Regeneración Muscular, Centro de Investigación sobre el Envejecimiento, Centro de Investigación y de Estudios Avanzados (CINVESTAV-IPN), Mexico City 14330, Mexico
  3. 3Laboratorio de Medicina Genómica, Departamento de Genética, Instituto Nacional de Rehabilitación–Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
  4. 4Subdirección de Enseñanza e Investigación, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico City 03100, Mexico
  5. 5Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Mexico City 07700, Mexico
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Abstract

Limb-girdle muscular dystrophy R6, formerly LGMD2F, is caused by mutations in the δ-sarcoglycan (Sgcd) gene and is characterized by progressive skeletal muscle degeneration. Although loss of δ-SG protein compromises sarcolemma stability, how δ-sarcoglycan deficiency reshapes inflammatory and metabolic gene programs across distinct skeletal muscles remains incompletely defined. Here, we profiled soleus and extensor digitorum longus (EDL) muscles from wild-type and Sgcd−/− mice treated with vehicle or (-)-epicatechin, a dietary flavanol with anti-inflammatory and antioxidant properties, using bulk RNA sequencing, pathway analysis, immune-cell deconvolution, and RT-qPCR validation. δ-sarcoglycan deficiency produced broad transcriptional remodeling while preserving baseline muscle-type identity. Across soleus and EDL, the dystrophic transcriptome was marked by interferon-associated inflammatory remodeling together with repression of oxidative and mitochondrial metabolic programs. Within this shared disease state, soleus displayed a stronger induced inflammatory component, including innate-sensing and macrophage-linked features. Computational deconvolution, which estimates immune-cell proportions from bulk transcriptomes (quanTIseq and mMCP-counter), supported genotype-dependent shifts in immune-cell signatures, with concordant monocyte/macrophage signals. Finally, (-)-epicatechin produced context-dependent transcriptional effects and attenuated a defined interferon/innate-sensing module in dystrophic soleus, as supported by RNA-seq and RT-qPCR. Together, these findings establish inflammatory remodeling with a prominent interferon component and oxidative metabolic repression as central transcriptional features of δ-sarcoglycan-deficient skeletal muscle, while revealing an amplified innate-sensing and immune-enriched module in dystrophic soleus that remains transcriptionally responsive to (-)-epicatechin treatment.

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Cite

BibTeXRIS
BibTeX
@article{cancinobello2026interferonassociated,
  title = {{Interferon-Associated Inflammatory Remodeling and Oxidative Metabolic Repression Define the Skeletal Muscle Transcriptomic Landscape of δ-Sarcoglycan Deficiency}},
  author = {Amairani Cancino-Bello and Mauricio Hernández-Somilleda and Erick Bahena-Culhuac and Estela G. García-González and Oscar Hernández-Hernández and Ramón M. Coral-Vázquez and J. Manuel Hernández-Hernández},
  journal = {Biomolecules},
  year = {2026},
  month = oct,
  doi = {10.3390/biom16101511},
  url = {https://www.mdpi.com/2218-273X/16/10/1511},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Interferon-Associated Inflammatory Remodeling and Oxidative Metabolic Repression Define the Skeletal Muscle Transcriptomic Landscape of δ-Sarcoglycan Deficiency
AU  - Amairani Cancino-Bello
AU  - Mauricio Hernández-Somilleda
AU  - Erick Bahena-Culhuac
AU  - Estela G. García-González
AU  - Oscar Hernández-Hernández
AU  - Ramón M. Coral-Vázquez
AU  - J. Manuel Hernández-Hernández
PY  - 2026
DA  - 2026/10/01
JO  - Biomolecules
DO  - 10.3390/biom16101511
UR  - https://www.mdpi.com/2218-273X/16/10/1511
AB  - Limb-girdle muscular dystrophy R6, formerly LGMD2F, is caused by mutations in the δ-sarcoglycan (Sgcd) gene and is characterized by progressive skeletal muscle degeneration. Although loss of δ-SG protein compromises sarcolemma stability, how δ-sarcoglycan deficiency reshapes inflammatory and metabolic gene programs across distinct skeletal muscles remains incompletely defined. Here, we profiled soleus and extensor digitorum longus (EDL) muscles from wild-type and Sgcd−/− mice treated with vehicle or (-)-epicatechin, a dietary flavanol with anti-inflammatory and antioxidant properties, using bulk RNA sequencing, pathway analysis, immune-cell deconvolution, and RT-qPCR validation. δ-sarcoglycan deficiency produced broad transcriptional remodeling while preserving baseline muscle-type identity. Across soleus and EDL, the dystrophic transcriptome was marked by interferon-associated inflammatory remodeling together with repression of oxidative and mitochondrial metabolic programs. Within this shared disease state, soleus displayed a stronger induced inflammatory component, including innate-sensing and macrophage-linked features. Computational deconvolution, which estimates immune-cell proportions from bulk transcriptomes (quanTIseq and mMCP-counter), supported genotype-dependent shifts in immune-cell signatures, with concordant monocyte/macrophage signals. Finally, (-)-epicatechin produced context-dependent transcriptional effects and attenuated a defined interferon/innate-sensing module in dystrophic soleus, as supported by RNA-seq and RT-qPCR. Together, these findings establish inflammatory remodeling with a prominent interferon component and oxidative metabolic repression as central transcriptional features of δ-sarcoglycan-deficient skeletal muscle, while revealing an amplified innate-sensing and immune-enriched module in dystrophic soleus that remains transcriptionally responsive to (-)-epicatechin treatment.
SN  - 2218-273X
ER  -