A single‐cell atlas of bovine skeletal muscle reveals mechanisms regulating intramuscular adipogenesis and fibrogenesis

Abstract Background Intramuscular fat (IMF) and intramuscular connective tissue (IMC) are often seen in human myopathies and are central to beef quality. The mechanisms regulating their accumulation remain poorly understood. Here, we explored the possibility of using beef cattle as a novel model for...

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Main Authors: Leshan Wang (Author), Peidong Gao (Author), Chaoyang Li (Author), Qianglin Liu (Author), Zeyang Yao (Author), Yuxia Li (Author), Xujia Zhang (Author), Jiangwen Sun (Author), Constantine Simintiras (Author), Matthew Welborn (Author), Kenneth McMillin (Author), Stephanie Oprescu (Author), Shihuan Kuang (Author), Xing Fu (Author)
Format: Book
Published: Wiley, 2023-10-01T00:00:00Z.
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100 1 0 |a Leshan Wang  |e author 
700 1 0 |a Peidong Gao  |e author 
700 1 0 |a Chaoyang Li  |e author 
700 1 0 |a Qianglin Liu  |e author 
700 1 0 |a Zeyang Yao  |e author 
700 1 0 |a Yuxia Li  |e author 
700 1 0 |a Xujia Zhang  |e author 
700 1 0 |a Jiangwen Sun  |e author 
700 1 0 |a Constantine Simintiras  |e author 
700 1 0 |a Matthew Welborn  |e author 
700 1 0 |a Kenneth McMillin  |e author 
700 1 0 |a Stephanie Oprescu  |e author 
700 1 0 |a Shihuan Kuang  |e author 
700 1 0 |a Xing Fu  |e author 
245 0 0 |a A single‐cell atlas of bovine skeletal muscle reveals mechanisms regulating intramuscular adipogenesis and fibrogenesis 
260 |b Wiley,   |c 2023-10-01T00:00:00Z. 
500 |a 2190-6009 
500 |a 2190-5991 
500 |a 10.1002/jcsm.13292 
520 |a Abstract Background Intramuscular fat (IMF) and intramuscular connective tissue (IMC) are often seen in human myopathies and are central to beef quality. The mechanisms regulating their accumulation remain poorly understood. Here, we explored the possibility of using beef cattle as a novel model for mechanistic studies of intramuscular adipogenesis and fibrogenesis. Methods Skeletal muscle single‐cell RNAseq was performed on three cattle breeds, including Wagyu (high IMF), Brahman (abundant IMC but scarce IMF), and Wagyu/Brahman cross. Sophisticated bioinformatics analyses, including clustering analysis, gene set enrichment analyses, gene regulatory network construction, RNA velocity, pseudotime analysis, and cell-cell communication analysis, were performed to elucidate heterogeneities and differentiation processes of individual cell types and differences between cattle breeds. Experiments were conducted to validate the function and specificity of identified key regulatory and marker genes. Integrated analysis with multiple published human and non‐human primate datasets was performed to identify common mechanisms. Results A total of 32 708 cells and 21 clusters were identified, including fibro/adipogenic progenitor (FAP) and other resident and infiltrating cell types. We identified an endomysial adipogenic FAP subpopulation enriched for COL4A1 and CFD (log2FC = 3.19 and 1.92, respectively; P < 0.0001) and a perimysial fibrogenic FAP subpopulation enriched for COL1A1 and POSTN (log2FC = 1.83 and 0.87, respectively; P < 0.0001), both of which were likely derived from an unspecified subpopulation. Further analysis revealed more progressed adipogenic programming of Wagyu FAPs and more advanced fibrogenic programming of Brahman FAPs. Mechanistically, NAB2 drives CFD expression, which in turn promotes adipogenesis. CFD expression in FAPs of young cattle before the onset of intramuscular adipogenesis was predictive of IMF contents in adulthood (R2 = 0.885, P < 0.01). Similar adipogenic and fibrogenic FAPs were identified in humans and monkeys. In aged humans with metabolic syndrome and progressed Duchenne muscular dystrophy (DMD) patients, increased CFD expression was observed (P < 0.05 and P < 0.0001, respectively), which was positively correlated with adipogenic marker expression, including ADIPOQ (R2 = 0.303, P < 0.01; and R2 = 0.348, P < 0.01, respectively). The specificity of Postn/POSTN as a fibrogenic FAP marker was validated using a lineage‐tracing mouse line. POSTN expression was elevated in Brahman FAPs (P < 0.0001) and DMD patients (P < 0.01) but not in aged humans. Strong interactions between vascular cells and FAPs were also identified. Conclusions Our study demonstrates the feasibility of beef cattle as a model for studying IMF and IMC. We illustrate the FAP programming during intramuscular adipogenesis and fibrogenesis and reveal the reliability of CFD as a predictor and biomarker of IMF accumulation in cattle and humans. 
546 |a EN 
690 |a Adipogenesis 
690 |a Fibro/adipogenic progenitor 
690 |a Fibrogenesis 
690 |a Intramuscular adipose tissue 
690 |a Single‐cell RNAseq 
690 |a Diseases of the musculoskeletal system 
690 |a RC925-935 
690 |a Human anatomy 
690 |a QM1-695 
655 7 |a article  |2 local 
786 0 |n Journal of Cachexia, Sarcopenia and Muscle, Vol 14, Iss 5, Pp 2152-2167 (2023) 
787 0 |n https://doi.org/10.1002/jcsm.13292 
787 0 |n https://doaj.org/toc/2190-5991 
787 0 |n https://doaj.org/toc/2190-6009 
856 4 1 |u https://doaj.org/article/e77cbf1d0fc54af0a6bb0da511022bf8  |z Connect to this object online.