# Gatm ablation disrupts spermatogenesis by impairing ribosome biogenesis and coupling defective steroid biosynthesis to immunoglobulin silencing

## TL;DR

This study shows that GATM is crucial for spermatogenesis, as its absence disrupts energy metabolism, ribosome function, and immune gene regulation in the testes.

## Contribution

The study reveals a novel role of GATM in spermatogenesis by linking creatine metabolism to ribosome biogenesis and immunoglobulin silencing.

## Key findings

- GATM deficiency causes testicular atrophy and disrupted spermatogenesis with cacospermia features.
- Transcriptomic analysis shows downregulated ribosome biogenesis and mitochondrial pathways in GATM-deficient testes.
- Immunoglobulin variable region genes are silenced specifically in GATM-deficient testes.

## Abstract

Glycine amidinotransferase (GATM) catalyzes the rate-limiting step in creatine biosynthesis, a pathway essential for cellular energy buffering in tissues with high metabolic demands. While its roles in muscle and brain are well established, the function of GATM in testicular development and spermatogenesis remains largely unexplored.

We generated a constitutive Gatm knockout mouse model using CRISPR/Cas9 technology. Comprehensive phenotypic characterization was performed through histological analysis, transmission electron microscopy (TEM), and transcriptomic profiling of whole testes and purified spermatozoa from Gatm, heterozygous (Gatm), and wild-type (WT) mice.

Gatm deficiency resulted in severe testicular atrophy, disorganized seminiferous tubules with epithelial thinning (reduced to 2–3 layers), and interstitial edema. Spermatogenesis was arrested, leading to dramatically reduced sperm density. Ultrastructural analysis revealed hallmark features of cacospermia, including mitochondrial depletion in the midpiece and nuclear vacuolization. Transcriptomic profiling demonstrated widespread dysregulation: testicular tissues showed downregulation of ribosome biogenesis and mitochondrial complex assembly pathways, whereas mature spermatozoa exhibited impaired steroid biosynthesis and ion transport. Notably, multiple immunoglobulin variable region genes (e.g., Ighv14-1, Igkv19-93) were completely transcriptionally silenced specifically in Gatm-deficient testes.

Our findings establish GATM as a multifunctional regulator of spermatogenesis, integrating creatine-dependent energy metabolism with translational capacity, organelle architecture, and immune-related gene regulation. The coordinated disruption of mitochondrial and ribosomal pathways provides a novel mechanistic framework for understanding the metabolic origins of male infertility.