Overload-mediated skeletal muscle hypertrophy is not impaired by loss of myofiber STAT3

Abstract

Although the signal pathways mediating muscle protein synthesis and degradation are well characterized, the transcriptional processes modulating skeletal muscle mass and adaptive growth are poorly understood. Recently, studies in mouse models of muscle wasting or acutely exercised human muscle have suggested a potential role for the transcription factor signal transducer and activator of transcription 3 (STAT3), in adaptive growth. Hence, in the present study we sought to define the contribution of STAT3 to skeletal muscle adaptive growth. In contrast to previous work, two different resistance exercise protocols did not change STAT3 phosphorylation in human skeletal muscle. To directly address the role of STAT3 in load-induced (i.e., adaptive) growth, we studied the anabolic effects of 14 days of synergist ablation (SA) in skeletal muscle-specific STAT3 knockout (mKO) mice and their floxed, wild-type (WT) littermates. Plantaris muscle weight and fiber area in the nonoperated leg (control; CON) was comparable between genotypes. As expected, SA significantly increased plantaris weight, muscle fiber cross-sectional area, and anabolic signaling in WT mice, although interestingly, this induction was not impaired in STAT3 mKO mice. Collectively, these data demonstrate that STAT3 is not required for overload-mediated hypertrophy in mouse skeletal muscle.

Keywords: STAT3; hypertrophy; resistance exercise; skeletal muscle.

Fig. 1.

Synergist ablation (SA) increases signal transducer and activator of transcription 3 (STAT3) phosphorylation in mouse skeletal muscle. A: relative phosphorylation and total STAT3 protein content in mouse skeletal muscle following 2 wk of SA (n = 6 muscles per group). WT, wild type; mKO, skeletal muscle-specific STAT3 knockout. B: relative STAT3 phosphorylation levels in human skeletal muscle pre- (P), 0 h post- (0), and 4 h post- (4) resistance exercise with either 1 or 5 min of interset rest (n = 7–8 per group). All samples were derived at the same time and processed in parallel. Values are means ± SE. *P < 0.05, **P < 0.01, and ***P < 0.001.

Fig. 2.

Synergist ablation (SA) increases skeletal muscle mass and fiber size. A: absolute mass of both control (CON) and SA plantaris. B: relative mass of both CON and SA plantaris. C: changes in average plantaris fiber cross-sectional area (CSA) following SA. D: representative images (red: laminin, blue: nuclei) and quantification of skeletal muscle fiber size (CSA) distribution of both CON and SA plantaris (white scale bar = 100 μm). Values are means ± SE (n = 6 muscles per group). *P < 0.05, **P < 0.01.

Fig. 3.

Synergist ablation (SA) promotes the activation of anabolic pathways. A–C: relative phosphorylation levels of downstream targets of phosphoinositide 3-kinase (PI3K) (Akt^T308), mechanistic target of rapamycin complex 2 (mTORC2) (Akt^S473), and mTORC1-S6K1 (S6^S235/S236 and S6^S240/S244) and mTORC1 (4E-BP1^T37/46) in both control (CON) and SA plantaris. D: total protein levels of the procatabolic protein myostatin under CON and SA conditions. All samples were derived at the same time and processed in parallel. Values are means ± SE (n = 6 muscles per group). *P < 0.05, **P < 0.01, and ***P < 0.001.