GDF15 modulates mitochondrial content and differentiation-associated metabolic remodeling in skeletal muscle cells.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro (C2C12 myoblasts) and animal (mouse) experimental study without human subjects
PubMed 42530072 · doi:10.1152/ajpendo.00438.2025
What was done
The authors investigated the role of growth differentiation factor 15 (GDF15) during myogenic differentiation and mitochondrial remodeling using mouse C2C12 myoblasts and bioinformatic pathway analyses. They conducted GDF15 knockdown and overexpression experiments to assess changes in mitochondrial content, mitochondrial DNA copy number, oxygen consumption, lactate production, and apoptosis. Downstream pathways involving peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), peroxisome proliferator-activated receptor delta (PPARδ), and estrogen-related receptor alpha (ERRα) were evaluated using gene silencing and transcriptomics. Additionally, male C57BL/6 mice underwent exercise training to measure soleus muscle GDF15 expression and aerobic performance.
What was found
The abstract reports directional findings without providing numerical values, sample sizes, or effect estimates. GDF15 mRNA, protein expression, and secretion increased during myogenesis concurrently with mitochondrial content, mitochondrial DNA copy number, and oxygen consumption. GDF15 knockdown lowered mitochondrial markers, increased lactate production, and triggered apoptosis, whereas overexpression produced the opposite effects. GDF15 enhancement of PGC1α transactivation and PPAR response element activity was abolished by silencing PPARδ or ERRα. In mice, exercise training elevated soleus GDF15 levels and improved aerobic performance.
Why it matters
These findings suggest that GDF15 functions locally as an autocrine regulator in skeletal muscle to promote oxidative capacity and mitochondrial biogenesis, rather than acting exclusively as a systemic metabolic signal.
Limits
The study is restricted to in vitro immortalized mouse cell lines (C2C12) and male mice, limiting direct translation to human physiology. No quantitative data, exact sample sizes (n), effect sizes, or confidence intervals are reported in the abstract. Female mice were not evaluated, and the relative contribution of autocrine versus systemic circulating GDF15 remains to be established in vivo.
Cited by
- supports GDF15 is secreted by cells in response to mitochondrial dysfunction or when cellular energy consumption exceeds sustainable levels.