Key result
Altering 47 identified genes drives up to ~345% skeletal muscle hypertrophy in mice.
Why the study?
Does experimental loss or gain-of-function of specific genes increase skeletal muscle mass in mice?
Systematic Review
Does experimental loss or gain-of-function of specific genes increase skeletal muscle mass in mice?
A systematic review identified 47 genes whose manipulation induces skeletal muscle hypertrophy in mice, primarily involving the Igf-Akt1-mTOR, myostatin-Smad, and angiotensin-bradykinin signaling pathways.
Highlights potential gene targets for muscle-wasting disorders; extends preclinical evidence but should not yet inform clinical practice.
Skeletal muscle mass differs greatly in mice and humans and this is partially inherited. To identify muscle hypertrophy candidate genes we conducted a systematic review to identify genes whose experimental loss or gain-of-function results in significant skeletal muscle hypertrophy in mice. We found 47 genes that meet our search criteria and cause muscle hypertrophy after gene manipulation. They are from high to small effect size: Ski, Fst, Acvr2b, Akt1, Mstn, Klf10, Rheb, Igf1, Pappa, Ppard, Ikbkb, Fstl3, Atgr1a, Ucn3, Mcu, Junb, Ncor1, Gprasp1, Grb10, Mmp9, Dgkz, Ppargc1ɑ (specifically the Ppargc1ɑ4 isoform), Smad4, Ltbp4, Bmpr1a, Crtc2, XIAP, Dgat1, Thra, Adrb2, Asb15, Cast, Eif2b5, Bdkrb2, Tpt1, Nr3c1, Nr4a1, Gnas, Pld1, Crym, Camkk1, Yap1, Inhba, Tp53inp2, Inhbb, Nol3, Esr1. Knock out, knock down, overexpression or a higher activity of these genes causes overall muscle hypertrophy as measured by an increased muscle weight or cross sectional area. The mean effect sizes range from 5% to 345% depending on the manipulated gene as well as the muscle size variable and muscle investigated. Bioinformatical analyses reveal that Asb15, Klf10, Tpt1 are most highly expressed hypertrophy genes in human skeletal muscle when compared to other tissues. Many of the muscle hypertrophy-regulating genes are involved in transcription and ubiquitination. Especially genes belonging to three signalling pathways are able to induce hypertrophy: a) Igf-Akt1-mTOR pathway, b) myostatin-Smad signalling and c) the angiotensin-bradykinin signalling pathway. The expression of several muscle hypertrophy-inducing genes and the phosphorylation of their protein products changes after human resistance and high intensity exercise, in maximally stimulated mouse muscle or in overloaded mouse plantaris.
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Verbrugge et al. (2018) conducted a systematic review in Skeletal muscle hypertrophy. Gene manipulation (loss or gain-of-function) was evaluated on Skeletal muscle hypertrophy (increased muscle weight or cross sectional area) (Mean effect sizes 5% to 345%). Experimental loss or gain-of-function of 47 identified genes caused skeletal muscle hypertrophy in mice, with mean effect sizes ranging from 5% to 345%.
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