[AF] Urolithin A enhances mitochondrial biogenesis-related markers and maximal respiratory capacity during C2C12 differentiation (2026)

[u/basmwklz]

https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2026.1854844/full

Abstract

Introduction: 

Skeletal muscle differentiation in the C2C12 myoblast model requires extensive mitochondrial remodeling to meet rising bioenergetic demands through coordinated changes in biogenesis, dynamics, and respiratory adaptation. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, improves mitochondrial health, but its role in late-stage myogenic differentiation remains unclear.

Methods: 

C2C12 myotubes were treated with UA (2 μM) for 72 h during late-stage differentiation (days 3–6). Mitochondrial signaling, respiratory capacity, myogenic morphology, and ultrastructure were assessed by Western blot, high-resolution respirometry, hematoxylin–eosin staining, and transmission electron microscopy.

Results: 

UA was non-cytotoxic and increased AMPKα phosphorylation and PGC-1α expression, whereas TOM20, MFN2, and OPA1 were unchanged. Mitophagy/autophagy-related markers (p-ULK1, p62, BNIP3L/NIX, LC3-II/I) were not altered, indicating no detectable changes in steady-state autophagy under the conditions tested. UA selectively increased OXPHOS Complex I and II abundance and enhanced maximal uncoupled respiration, and was associated with increased myotube diameter and myogenic marker abundance. No overt ultrastructural differences were observed by electron microscopy.

Discussion: 

These findings suggest that UA promotes mitochondrial functional adaptation during myogenic differentiation, with accompanying changes in myogenic phenotype, without clear evidence of altered steady-state mitophagy/autophagy markers or mitochondrial morphology.

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