METTL3-mediated m6A modification alleviates skeletal muscle atrophy in ALS by regulating ACSL1-dependent triglyceride metabolism
- 1Shandong second medical university
Abstract
Skeletal muscle-intrinsic defects are increasingly recognized as critical contributors to the pathogenesis of amyotrophic lateral sclerosis (ALS), yet the underlying molecular mechanisms remain poorly understood. N6-methyladenosine (m6A) is the most abundant post-transcriptional RNA modification in mammalian mRNAs that plays important regulatory roles in diverse physiological and pathological processes, however its role in ALS-associated skeletal muscle atrophy remains unknown. Here we found that global m6A methylation and the expression of its methyltransferase METTL3 are reduced in the skeletal muscle of hSOD1G93A transgenic ALS mice. Multi-omics analyses reveal that m6A dysregulation is closely associated with impaired triglyceride metabolism. Functionally, METTL3 promotes triglyceride accumulation in ALS skeletal muscle in an m6A-dependent manner; overexpression of METTL3 in ALS myotubes improves energy supply and alleviates muscle atrophy by promoting triglyceride accumulation. In vivo overexpression of Mettl3 in skeletal muscle attenuates muscle atrophy, improves motor performance, and prolongs survival of ALS mice. Mechanistically, we identify the fatty acid activation enzyme ACSL1 as a key downstream effector of METTL3-mediated regulation of triglyceride metabolism. METTL3-mediated m6A modification promotes the expression of Acsl1 by enhancing its mRNA stability. Further investigation revealed that the regulatory effect of m6A on Acsl1 expression depends on the m6A reader protein IGF2BP2. Collectively, our findings establish m6A modification as a critical regulator of skeletal muscle atrophy in ALS by maintaining triglyceride metabolic homeostasis, highlighting a promising therapeutic target for ALS.
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BibTeX
@misc{yan2026mettl3mediated,
title = {{METTL3-mediated m6A modification alleviates skeletal muscle atrophy in ALS by regulating ACSL1-dependent triglyceride metabolism}},
author = {Q. Yan and L. Zhang and X. Bai and Y. Guan and H. Zhang and J. Liu and B. Zhuang and M. Li and X. Zhang and X. Chen and X. Ma and C. Xu and H. Yang and X. Huang and F. Zhou and Y. Chen},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.759261},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.759261v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - METTL3-mediated m6A modification alleviates skeletal muscle atrophy in ALS by regulating ACSL1-dependent triglyceride metabolism
AU - Q. Yan
AU - L. Zhang
AU - X. Bai
AU - Y. Guan
AU - H. Zhang
AU - J. Liu
AU - B. Zhuang
AU - M. Li
AU - X. Zhang
AU - X. Chen
AU - X. Ma
AU - C. Xu
AU - H. Yang
AU - X. Huang
AU - F. Zhou
AU - Y. Chen
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.759261
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.759261v1
AB - Skeletal muscle-intrinsic defects are increasingly recognized as critical contributors to the pathogenesis of amyotrophic lateral sclerosis (ALS), yet the underlying molecular mechanisms remain poorly understood. N6-methyladenosine (m6A) is the most abundant post-transcriptional RNA modification in mammalian mRNAs that plays important regulatory roles in diverse physiological and pathological processes, however its role in ALS-associated skeletal muscle atrophy remains unknown. Here we found that global m6A methylation and the expression of its methyltransferase METTL3 are reduced in the skeletal muscle of hSOD1G93A transgenic ALS mice. Multi-omics analyses reveal that m6A dysregulation is closely associated with impaired triglyceride metabolism. Functionally, METTL3 promotes triglyceride accumulation in ALS skeletal muscle in an m6A-dependent manner; overexpression of METTL3 in ALS myotubes improves energy supply and alleviates muscle atrophy by promoting triglyceride accumulation. In vivo overexpression of Mettl3 in skeletal muscle attenuates muscle atrophy, improves motor performance, and prolongs survival of ALS mice. Mechanistically, we identify the fatty acid activation enzyme ACSL1 as a key downstream effector of METTL3-mediated regulation of triglyceride metabolism. METTL3-mediated m6A modification promotes the expression of Acsl1 by enhancing its mRNA stability. Further investigation revealed that the regulatory effect of m6A on Acsl1 expression depends on the m6A reader protein IGF2BP2. Collectively, our findings establish m6A modification as a critical regulator of skeletal muscle atrophy in ALS by maintaining triglyceride metabolic homeostasis, highlighting a promising therapeutic target for ALS.
ER -