---
title: "ULK1 and ULK2 Coordinate Autophagy and mTORC1 to Limit Skeletal Myofiber Growth"
id: "biorxiv-16-ulk1-and-ulk2-restrain-skeletal-myofiber-growth-by-balancing-protein-synthesis"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-16-ulk1-and-ulk2-restrain-skeletal-myofiber-growth-by-balancing-protein-synthesis"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.06.749722v1?rss=1"
published_at: "2026-09-10T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# ULK1 and ULK2 Coordinate Autophagy and mTORC1 to Limit Skeletal Myofiber Growth
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-16-ulk1-and-ulk2-restrain-skeletal-myofiber-growth-by-balancing-protein-synthesis
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.06.749722v1?rss=1)
- **Published At:** 2026-09-10T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study tested roles for the autophagy‑initiating kinases **ULK1** and **ULK2** in regulating skeletal muscle protein metabolism, using lifelong and short‑term skeletal muscle–specific knockouts in mice and plasmid miRNA electroporation in adult muscle. - Lifelong Ulk1/2 skeletal muscle deficiency (Ulk1/2skmDKO) markedly impaired autophagy flux, as LC3‑II accumulated with colchicine only in wild‑type mice (P<0.001). - Lifelong deficiency increased central nucleation of fibers (from 0.1% to 4.5% in females, and from 0.8% to 22.7% in males, P<0.001), predominantly affecting MyHC type 2b fibers, and reduced force in male dorsiflexors and plantar flexors (≈20%, P<0.01) and female plantar flexors (≈24%, P<0.01). - Despite impaired quality and function, lifelong Ulk1/2 loss produced robust hypertrophy: fiber diameters across major MyHC types increased (10–15% in males; 14–20% in females, P<0.05) in tibialis anterior and soleus. - Short‑term Ulk1/2 deficiency (up to 4 weeks) in adult muscle also produced myofiber hypertrophy (~13%, P<0.05) but without force loss or increased central nucleation, indicating an early window of preserved muscle quality. - Protein metabolism measures showed higher myofibrillar protein synthesis (Ksyn +23%, P<0.05) and reduced mitochondrial and sarcoplasmic protein degradation (Kdeg −16% and −14%, P=0.09 and P<0.05, respectively) in Ulk1/2‑deficient muscle. - Hypertrophy in Ulk1/2‑deficient muscle was associated with increased **mTORC1** signaling independent of AKT activation. - Overall, ULK1 and ULK2 jointly sustain **autophagy** and restrain mTORC1‑driven protein synthesis to balance protein turnover; lifelong deficiency increases size but reduces muscle quality, while short‑term loss permits growth without immediate functional decline. - The authors propose ULK1/2 as a regulatory node of protein turnover and suggest these kinases merit further study as potential therapeutic targets for atrophy and weakness. Funding sources and competing interest statements were reported in the source.
## Clinical Analysis & Structured Key Points
Background Skeletal muscle is vital for mobility and metabolic regulation, impacting independence and overall health. Increases in skeletal muscle mass and contractile function during development, and their maintenance during adulthood and aging, rely on an intricate coordination between protein synthesis and degradation processes that remains incompletely understood. Here, we investigated a potential role for the autophagy-initiating kinases ULK1 and ULK2 in broadly modulating protein metabolism in skeletal muscle. Methods Studies were conducted in young (4-6 wk-old) and adult (7-10 mo.-old) mice with skeletal muscle-specific knockout of Ulk1 and Ulk2 (i.e., Ulk1/2skmDKO) and wild-type littermates (WT). Short-term deficiency of these proteins was achieved via electroporation of plasmids (encoding specific microRNAs targeting Ulk1 and Ulk2) into muscles of 4 mo.-old wild-type mice. Protein metabolism was assessed via deuterium oxide (D2O) labeling, whereas anabolic signaling was investigated under insulin and leucine administration. Results Lifelong Ulk1/2 deficiency markedly impaired autophagy flux (i.e., LC3-II accumulated with colchicine treatment only in wild-type mice, P<0.001), compromised muscle quality, as evidenced by an increase in centrally nucleated fibers (from 0.1% to 4.5% in females, and from 0.8% to 22.7% in males (P<0.001), primarily involving MyHC type 2b fibers) and impaired force of dorsiflexors and plantar flexors in males (20%, P<0.01), and plantar flexors in females (24%, P<0.01). Despite these deficits, Ulk1/2 deficiency promoted robust muscle hypertrophy, evidenced by increased diameters of all major MyHC fiber types in the tibialis anterior and soleus muscles (i.e., by 10-15% in males, and 14-20% in females, P<0.05). Short-term deficiency (up to 4 weeks) of Ulk1/2 in adult skeletal muscle, however, led to myofiber hypertrophy (13%, P<0.05) without impairments in force or changes in central nucleation of fibers, pointing to an initial period of muscle quality preservation. Mechanistically, Ulk1/2 deficiency led to elevated myofibrillar protein synthesis (23% higher Ksyn, P<0.05) and decreased mitochondrial and sarcoplasmic protein degradation (16% and 14% lower Kdeg, P=0.09 and P<0.05, respectively). Further mechanistic studies revealed that hypertrophy was accompanied by enhanced mTORC1 activity independent of AKT in Ulk1/2-deficient muscle. Conclusions These results indicate that ULK1 and ULK2 jointly sustain autophagy and limit mTORC1-driven protein synthesis to govern skeletal muscle protein metabolism, with lifelong deficiency increasing muscle size at the expense of quality and function, while short-term deficiency permits hypertrophy without impairment. These findings identify ULK1/2 as a novel node coordinating protein turnover in skeletal muscle, warranting investigation as a therapeutic strategy for atrophy and weakness.
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