Genes Whose Gain or Loss-Of-Function Increases Skeletal Muscle Mass in Mice: A Systematic Literature Review

Abstract

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, Ppargc1a (specifically the Ppargc1a4 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 signaling pathways are able to induce hypertrophy: (a) Igf1-Akt-mTOR pathway, (b) myostatin-Smad signaling, and (c) the angiotensin-bradykinin signaling 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.

Keywords: GWAS; gene manipulation; hypertrophy; mutation; myostatin; resistance exercise; sarcopenia; skeletal muscle.

Figure 1

Gene knock-in or overexpression increases muscle weight and cross-sectional area (CSA). Increase in muscle weight (A) and fiber or muscle CSA (B) differs across genes and between muscles. Individual muscles are color-coded as follows: $•$ Gastrocnemius, $•$ Soleus, $•$ Tibialis anterior, $•$ Quadriceps, $•$ Extensor digitorum longus, $•$ Other. Data is based on values collected in Supplementary Table S2.

Figure 2

Gene knock out or loss-of-function increases muscle weight and cross-sectional area (CSA). Increase in muscle weight (A) and fiber or muscle CSA (B) after gene knock out differs across genes and between muscles. Individual muscles are color-coded as follows: $•$ Gastrocnemius, $•$ Soleus, $•$ Tibialis anterior, $•$ Quadriceps, $•$ Extensor digitorum longus, $•$ Other. Data is based on values collected in Supplementary Table S2.

Figure 3

Expression of muscle mass regulating genes after resistance exercise. Transcriptome data GSE23244 from Vissing and Schjerling (2014) was accessed to discover which muscle mass regulating genes are induced or repressed 2.5 h or 5 h relative to resting value after a bout of resistance exercise. (A) Expression of genes whose overexpression or activation increases muscle mass in mice. (B) Expression of genes whose knock out increases muscle mass. Genes whose mean expression increased or decreased by more than 10% are shown in this figure. ^aDifferent at 2.5 h compared to pre-training, ^bDifferent compared to control group at 2.5 h, ^cDifferent at 5 h compared to pre-training, ^dDifferent compared to control group at 5 h (n = 6). Note that the data for pan PPARGC1A are shown. However, muscle hypertrophy is only stimulated by the PGC-1α4 protein isoform (Ruas et al., 2012).

Figure 4

Relative mRNA expression of Igf1 (A), Akt1 (B), Mstn (C), and Bmpr1a (D) in synergist ablation-overloaded mouse plantaris muscle. Igf1, Akt1, Mstn change their expression which is consistent with the hypertrophy of the plantaris. In contrast, Bmpr1a did not change its expression as expected as the overexpression of Bmpr1a causes hypertrophy (Sartori et al., 2013) whilst its expression decreased in the hypertrophying plantaris (see Supplementary Table S3, worksheet 7 for further figures). Original data derived from microarray dataset GSE47098 data from Chaillou et al. (2013).