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Comparison of Wild type and Pofut1-deleted skeletal muscle

ABSTRACT: Pofut1 is an essential gene that glycosylates proteins containing EGF-like repeats, including Notch Receptors (NotchRs). Work in mice and in Drosophila has shown that O-fucosylation by Pofut1 is required for NotchR ligands to bind to and activate NotchRs. As such, Pofut1 deletion in skeletal myofibers allows for an analysis of potential functions and molecular changes of Pofut1 in skeletal muscle that derive from its expression in skeletal myofibers. In this study we compared gene expression profiles between quadriceps muscles in mice where Protein O-fucosyltransferase 1 (Pofut1) was deleted specifically in skeletal myofibers via use of a human skeletal alpha actin Cre transgene (Scre) and a loxP flanked Pofut1 gene (SCreFF) and mice which bore the only the Scre transgene but did not have floxed Pofut1 alleles (SCre++). Muscles were dissected from two month-old mice. We have found that SCreFF mice develop reduced muscle size and strength with age. These changes are analogous to sarcopenic changes that normally occur in aged muscles, where Pofut1 expression is also reduced. These phenotypes begin at and beyond 3 months and are very significant by 6 months of age. The goal of this study was to capture molecular changes that precede the reductions in muscle size and strength, some of which were validated by qRT-PCR.

ORGANISM(S): Mus musculus

PROVIDER: GSE80145 | GEO | 2017/03/27

SECONDARY ACCESSION(S): PRJNA318030

REPOSITORIES: GEO

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Project description:Purpose: Despite demonstrating that the overall effect of long-term rapamycin-treatment is overwhelmingly positive in aging skeletal muscle, we observed muscle-specificity in the responsiveness to rapamycin, leading us to hypothesize that the primary drivers of age-related muscle loss and therefore effective intervention strategies may differ between muscles. To address this question and dissect the key signaling nodes associated with mTORC1-driven muscle aging, we created a comprehensive multi-muscle gene expression atlas in adult, sarcopenic and rapamycin-treated mice using RNA-seq. Methods: To examine the impact of long-term rapamycin treatment, male C57BL/6 mice were fed encapsulated rapamycin incorporated into a standardized AIN93M diet at 42 ppm (i.e. mg per kg of food), corresponding to a dose of ~4 mg·kg-1·day-1, from 15- to 30-months of age. This dose of rapamycin has been shown to extend lifespan maximally in male C57BL/6 mice. We performed RNA-seq on gastrocnemius (GAS), tibialis anterior (TA), triceps brachii (TRI) and soleus (SOL) muscles from each of six mice for 10m, 30m and 30mRM groups. The four muscle types were chosen to encompass fore- and hindlimb locations (e.g. TRI and GAS); slow and fast contraction properties (e.g. SOL and GAS); anterior and posterior positioning (e.g. TA and GAS) and the extent of protection by rapamycin (TA and TRI: protected; SOL: partiallly protected; GAS: not protected). Results: Age-related gene expression changes were remarkably consistent across the four different muscles, varying only in magnitude. Despite having the smallest age-related muscle loss of the four muscles, TA had the strongest age-related gene expression response which was associated with an increased reinnervation response. Despite the strong between-muscle commonality of age-related changes, gene expression responses to prolonged rapamycin treatment differed substantially between muscles. Rapamycin partially reversed many age-related changes in mRNA expression in the TA and TRI, but not in SOL or GAS muscle. Principle component analysis (PCA) showed that rapamycin had common 'anti-aging' effects on all muscles, while also exerting muscle-specific pro-aging effects on muscles not protected by rapamycin. Conclusions: Sustained, muscle fiber-specific mTORC1 activity drives sarcopenia-like gene expression programs, and the hyperactive mTORC1 seen in sarcopenic muscle may therefore contribute to sarcopenia.

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Comparison of Wild type and Pofut1-deleted skeletal muscle

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