Stanniocalcin‐2 inhibits skeletal muscle growth and is upregulated in functional overload‐induced hypertrophy

Figures

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  FIGURE 1. Stc2 effects on muscle weight. Plots illustrate the relationship between weight of five hindlimb muscles (y‐axis, weight residuals adjusted for sex plus overall mean) and the genotype of mice (x‐axis, wild type [WT, n = 15] or knockout [Stc2 −/− , n = 21]). Red symbols—female, black—male. The horizontal line represents the mean value, the error bars represent standard deviation. p‐values of general linear model (with sex and genotype as factors) are shown for the genotype effect.

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  FIGURE 2. Effects of Stc2 on muscle fibers. (a) Representative micrographs of wild‐type (WT) and Stc2 −/− EDL muscles stained with antibodies against laminin. (b) Representative micrographs of EDL muscles stained with antibodies against type IIa myosin. (c) Relative frequency of 16,366 EDL muscle fibers from wild‐type (n = 8) and Stc2 −/− (n = 7) males by size. Chi‐squared p‐values of the within‐bin actual versus expected number of fibers comparison were adjusted for the number of bins; *p < 0.05, **p < 0.01. (d) Cross‐sectional area (CSA) of Type IIA fibers and (e) proportion of Type IIA fibers in EDL muscle. Mean and SEM.

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  FIGURE 3. The IGF axis components in the overload‐induced muscle hypertrophy and myostatin deficiency model. (a) Concentration of STC2 following unilateral 4‐week functional overload. (b) Plantaris weight and concentration of the ligands and regulatory components of the IGF axis following 4‐week functional overload. (c) STC2 concentration in myostatin deficient BEH mice and mice heterozygous for wildtype myostatin BEH C/+. (d) Plantaris weight and concentration of the ligands and regulatory components of the IGF axis in myostatin deficient BEH mice and mice heterozygous for wildtype myostatin BEH C/+. Data are presented as mean and SD adjusted to the mean of the Control (x̄Control) or BEH C/+ (x̄BEH C/+) group of the corresponding variable. *p < 0.05, † p < 0.01, ‡ p < 0.0001 compared with the corresponding Control and BEH C/+ in (b) and (d), respectively. A paired t‐test was carried out in (a) and (b) and unpaired t‐test in (c) and (d). Numbers in (b) and (d) indicate sample size.

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  FIGURE 4. The role of STC2 in IGF axis mediated growth signaling in skeletal muscle. Intracellular signaling is triggered by the IGF1 binding to its receptor, IGF1R, and leads to upregulation of protein synthesis and growth. However, the pericellular availability of biologically active IGF1 is tightly regulated. The IGF binding proteins (IGFBP) sequester the IGF1 into the IGF1:IGFBP complex. The complex cannot interact with the receptor, but it creates a reservoir from which IGF1 can be mobilized by a specialized proteinase, PAPP‐A. PAPP‐A is tethered to the sarcolemma via glycosaminoglycans (GAG), therefore upon IGFBP cleavage biologically active IGF1 is released in close proximity to the receptor. In wildtype muscle fiber (WT), STC2 inhibits PAPP‐A activity suppressing the intracellular signaling of IGF1. Deletion of stanniocalcin‐2 abrogates this inhibitory mechanism in the Stc2 −/− muscle fibers allowing the PAPP‐A to mobilize IGF1 from the IGF1:IGFBP complex more efficiently. This potentiates the growth promoting IGF1 signaling and stimulates muscle fiber hypertrophy.