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Cited by 119Muscle Physiology and DisordersMuscle metabolism and nutritionTGF-β signaling in diseases

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JNK regulates muscle remodeling via myostatin/SMAD inhibition

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Lessard, Sarah J., MacDonald, Tara L., Pathak, Prerana, Han, Myoung Sook, Coffey, Vernon G., Edge, Johann, Rivas, Donato A., Hirshman, Michael F., Davis, Roger J., Goodyear, Laurie J.·2018·Nature Communications
DOI 10.1038/s41467-018-05439-3PMC PMC6072737
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Abstract

Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass. Conversely, when muscle JNK activation is suppressed, an alternative remodeling program is initiated, resulting in smaller, more oxidative muscle fibers, and enhanced aerobic fitness. When muscle is exposed to mechanical stress, JNK initiates muscle growth via phosphorylation of the transcription factor, SMAD2, at specific linker region residues leading to inhibition of the growth suppressor, myostatin. In human skeletal muscle, this JNK/SMAD signaling axis is activated by resistance exercise, but not endurance exercise. We conclude that JNK acts as a key mediator of muscle remodeling during exercise via regulation of myostatin/SMAD signaling.

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Figures

Fig. 1 Loss of JNK in skeletal muscle enhances adaptation to endurance training. Muscle-specific JNK knockout mice (mJNKKO) and controls (WT; MCK-Cre−/+) were placed in voluntary wheel-running cages for 10 weeks (Exercise-trained; EXT). A separate cohort of mice remained in cages without running wheels (Sedentary; SED) and acted as controls. a Exercise capacity was similar in WT and mJNKKO mice that were sedentary, but was higher in mJNKKO mice after training. b, c Histological analysis was performed on the red gastrocnemius muscle from sedentary and exercise-trained mJNKKO mice and controls. Staining with antibodies against CD31 (red) (b) was used to calculate capillary density (c). d–f Sections were stained with wheat germ agglutinin (WGA; green) and myosin heavy chain type I (red) antibodies (f) to determine fiber type (e) and cross-sectional area (f). *P < 0.05 vs SED of the same genotype by two-way ANOVA and Sidak’s post hoc testing. Scale bars represent 100 µm. Each data point represents the results from an individual animal. Bar plots indicate mean ± SEM for all data
Fig. 1 Loss of JNK in skeletal muscle enhances adaptation to endurance training. Muscle-specific JNK knockout mice (mJNKKO) and controls (WT; MCK-Cre−/+) were placed in voluntary wheel-running cages for 10 weeks (Exercise-trained; EXT). A separate cohort of mice remained in cages without running wheels (Sedentary; SED) and acted as controls. a Exercise capacity was similar in WT and mJNKKO mice that were sedentary, but was higher in mJNKKO mice after training. b, c Histological analysis was performed on the red gastrocnemius muscle from sedentary and exercise-trained mJNKKO mice and controls. Staining with antibodies against CD31 (red) (b) was used to calculate capillary density (c). d–f Sections were stained with wheat germ agglutinin (WGA; green) and myosin heavy chain type I (red) antibodies (f) to determine fiber type (e) and cross-sectional area (f). *P < 0.05 vs SED of the same genotype by two-way ANOVA and Sidak’s post hoc testing. Scale bars represent 100 µm. Each data point represents the results from an individual animal. Bar plots indicate mean ± SEM for all dataCC BY · PubMed Central
Fig. 2 JNK is necessary for muscle hypertrophy with overload. The distal portion of the gastrocnemius muscle was surgically removed from one limb in muscle JNK knockout (mJNKKO) mice and wild-type controls (WT; MCK-Cre−/+) to induce functional overload (OVL) of the plantaris muscle. The contralateral limb served as control (CON). a Fourteen days following overload surgery, the plantaris muscles were removed and wet weight was recorded. b Sections from plantaris muscles were stained with wheat germ agglutinin (green) for the calculation of fiber cross-sectional area (CSA). Scale bar represents 100 µm. c, d Average CSA was calculated (c) from the Control and Overload muscles from both genotypes, and fiber size distribution was plotted (d). *P < 0.05, **P < 0.01 vs Control from the same genotype by two-way ANOVA and Sidak’s post hoc testing. Main effects of genotype are displayed with P-values. Each data point represents the results from an individual animal. Bar plots indicate mean ± SEM for all data
Fig. 2 JNK is necessary for muscle hypertrophy with overload. The distal portion of the gastrocnemius muscle was surgically removed from one limb in muscle JNK knockout (mJNKKO) mice and wild-type controls (WT; MCK-Cre−/+) to induce functional overload (OVL) of the plantaris muscle. The contralateral limb served as control (CON). a Fourteen days following overload surgery, the plantaris muscles were removed and wet weight was recorded. b Sections from plantaris muscles were stained with wheat germ agglutinin (green) for the calculation of fiber cross-sectional area (CSA). Scale bar represents 100 µm. c, d Average CSA was calculated (c) from the Control and Overload muscles from both genotypes, and fiber size distribution was plotted (d). *P < 0.05, **P < 0.01 vs Control from the same genotype by two-way ANOVA and Sidak’s post hoc testing. Main effects of genotype are displayed with P-values. Each data point represents the results from an individual animal. Bar plots indicate mean ± SEM for all dataCC BY · PubMed Central
Fig. 3 SMAD-linker and JNK phosphorylation with exercise and muscle contraction in mice. a ICR mice underwent moderate intensity treadmill running for 15, 30, or 60 min and gastrocnemius muscles were collected. Control (rest) mice did not undergo treadmill running. Western blotting was used to determine exercise-induced signal transduction. Data from N = 3 mice/group are shown. b Electrodes were used to stimulate the lower hindlimb muscles from ICR mice [C; contracted]. The contralateral limb was unstimulated and acted as a control [B; basal]. Data from N = 3 mice/group are shown. c Both soleus muscles were rapidly removed from mice and attached to a force tranducer in oxygenated Kreb’s Henseleit Buffer. One muscle from each mouse was left at resting tension and acted as a basal control [Basal; B], while contralateral muscle was stretched for 10 min at a force of 0.12 N [Stretched; S]. N = 6 independent experiments were performed, and individual results from N = 3 are shown. pSMAD2L, linker region phosphorylated SMAD2; pJNK, phosphorylated (active) C-Jun N-terminal Kinase; pAMPK, phosphorylated (T172) AMP-activated protein kinase; pERK, phosphorylated extracellular signal regulated kinase; pP38, phosphorylated P38 Mitogen-Activated Protein Kinase; SMAD2, Total SMAD2. Images obtained using stain-free gel technology (Bio-Rad) that allows for total protein visualization and quantification are shown as a loading control (Loading)
Fig. 3 SMAD-linker and JNK phosphorylation with exercise and muscle contraction in mice. a ICR mice underwent moderate intensity treadmill running for 15, 30, or 60 min and gastrocnemius muscles were collected. Control (rest) mice did not undergo treadmill running. Western blotting was used to determine exercise-induced signal transduction. Data from N = 3 mice/group are shown. b Electrodes were used to stimulate the lower hindlimb muscles from ICR mice [C; contracted]. The contralateral limb was unstimulated and acted as a control [B; basal]. Data from N = 3 mice/group are shown. c Both soleus muscles were rapidly removed from mice and attached to a force tranducer in oxygenated Kreb’s Henseleit Buffer. One muscle from each mouse was left at resting tension and acted as a basal control [Basal; B], while contralateral muscle was stretched for 10 min at a force of 0.12 N [Stretched; S]. N = 6 independent experiments were performed, and individual results from N = 3 are shown. pSMAD2L, linker region phosphorylated SMAD2; pJNK, phosphorylated (active) C-Jun N-terminal Kinase; pAMPK, phosphorylated (T172) AMP-activated protein kinase; pERK, phosphorylated extracellular signal regulated kinase; pP38, phosphorylated P38 Mitogen-Activated Protein Kinase; SMAD2, Total SMAD2. Images obtained using stain-free gel technology (Bio-Rad) that allows for total protein visualization and quantification are shown as a loading control (Loading)CC BY · PubMed Central
Fig. 4 JNK is the upstream kinase for SMAD2 linker phosphorylation in muscle. a–c EDL and TA muscles from wild-type control (WT; MCK-Cre−/+) and muscle-specific JNK1/2 knockout mice (KO) were stimulated via in vitro (EDL) and in situ (TA) contraction. Immunoblotting of phosphorylated and total SMAD2 and JNK was performed (a). SMAD2-linker (SMAD2L) phosphorylation in response to in vitro contraction (b) and in situ contraction (c) was blunted in muscle JNK knockout mice. Each data point represents the basal and contraction results from an individual animal joined by a line. *P < 0.05, ***P < 0.01 vs Basal from the same genotype by repeated measures two-way ANOVA and Sidak’s post hoc testing. Main effects of genotype are displayed with P-values. d C2C12 myoblasts were treated with the JNK activator anisomycin (5 μM) for 30 min. e C2C12 myoblasts were transfected with plasmids expressing constitutively active JNK1, JNK2, or a combination of JNK1 and 2. Empty vector (EV) transfected cells were used as a control. f The ability of JNK to directly phosphorylate SMAD2 was assessed using an in vitro kinase assay. C2C12 lysates expressing empty vector (EV), or constitutively active JNK1 or JNK2 were purified by FLAG immunoprecipitation and incubated with recombinant SMAD2 and SMAD3 proteins. For tissue culture experiments (d–f), three independent experiments were performed and the data from one representative experiment, including all replicates is displayed. In all experiments, JNK activation (pJNK) and SMAD2 linker phosphorylation (pSMAD2L) were assessed by immunoblotting. Images obtained using stain-free gel technology (Bio-Rad) that allows for total protein visualization and quantification are shown as a loading control (Loading). pJNK phosphorylated (active) C-Jun N-terminal Kinase, pSMAD2L, linker-region phosphorylated SMAD2; SMAD2, total SMAD2; pP38, phosphorylation P38 MAPK; pERK, phosphorylated extracellular signal regulated kinase
Fig. 4 JNK is the upstream kinase for SMAD2 linker phosphorylation in muscle. a–c EDL and TA muscles from wild-type control (WT; MCK-Cre−/+) and muscle-specific JNK1/2 knockout mice (KO) were stimulated via in vitro (EDL) and in situ (TA) contraction. Immunoblotting of phosphorylated and total SMAD2 and JNK was performed (a). SMAD2-linker (SMAD2L) phosphorylation in response to in vitro contraction (b) and in situ contraction (c) was blunted in muscle JNK knockout mice. Each data point represents the basal and contraction results from an individual animal joined by a line. *P < 0.05, ***P < 0.01 vs Basal from the same genotype by repeated measures two-way ANOVA and Sidak’s post hoc testing. Main effects of genotype are displayed with P-values. d C2C12 myoblasts were treated with the JNK activator anisomycin (5 μM) for 30 min. e C2C12 myoblasts were transfected with plasmids expressing constitutively active JNK1, JNK2, or a combination of JNK1 and 2. Empty vector (EV) transfected cells were used as a control. f The ability of JNK to directly phosphorylate SMAD2 was assessed using an in vitro kinase assay. C2C12 lysates expressing empty vector (EV), or constitutively active JNK1 or JNK2 were purified by FLAG immunoprecipitation and incubated with recombinant SMAD2 and SMAD3 proteins. For tissue culture experiments (d–f), three independent experiments were performed and the data from one representative experiment, including all replicates is displayed. In all experiments, JNK activation (pJNK) and SMAD2 linker phosphorylation (pSMAD2L) were assessed by immunoblotting. Images obtained using stain-free gel technology (Bio-Rad) that allows for total protein visualization and quantification are shown as a loading control (Loading). pJNK phosphorylated (active) C-Jun N-terminal Kinase, pSMAD2L, linker-region phosphorylated SMAD2; SMAD2, total SMAD2; pP38, phosphorylation P38 MAPK; pERK, phosphorylated extracellular signal regulated kinaseCC BY · PubMed Central
Fig. 5 JNK inhibits myostatin/SMAD activity. a HEK293 cells were transfected with a SMAD-binding element (SBE4) luciferase reporter construct in the absence or presence of active JNK. 16 h following transfection, the cells were treated with 20 nM myostatin or Vehicle control for 4 h. Cells were lysed and analyzed for luciferase activity. b Western immunoblotting analysis was performed on whole-cell lysates from the luciferase experiment to assess levels of SMAD2 and JNK phosphorylation. c C2C12 myoblasts were transfected with empty vector (Control) or plasmids expressing active JNK fusion proteins. 24 h following transfection, the cells were treated with 20 nM myostatin or Vehicle for 30 min. Cytosolic and nuclear fractions were collected and immunoblotting was performed to assess the localization of total and phosphorylated SMAD2 and JNK. d,e Nuclear accumulation of phosphorylated SMAD2 (SMAD2C) (d) and total SMAD2 (e) were quantified. Data are representative of three independent experiments (a, c) and the data displayed are replicates from one representative experiment. pSMAD2-C, C-terminus phosphorylated SMAD2; pJNK, phosphorylated (active) c-Jun N-terminal Kinase; pSMAD2L, linker-region phosphorylated SMAD2; SMAD2/3, total SMAD2/3; GAPDH is a cytosolic loading control; Lamin A/C is a nuclear loading control. Stain-free gel images (Bio-Rad) are also shown as a loading control (Loading). *P < 0.05, **P < 0.001, ***P < 0.0001 vs vehicle treatment by two-way ANOVA with Sidak’s post hoc testing. Main effects of genotype (JNK activity) are displayed. Bar plots indicate mean ± SEM for all data
Fig. 5 JNK inhibits myostatin/SMAD activity. a HEK293 cells were transfected with a SMAD-binding element (SBE4) luciferase reporter construct in the absence or presence of active JNK. 16 h following transfection, the cells were treated with 20 nM myostatin or Vehicle control for 4 h. Cells were lysed and analyzed for luciferase activity. b Western immunoblotting analysis was performed on whole-cell lysates from the luciferase experiment to assess levels of SMAD2 and JNK phosphorylation. c C2C12 myoblasts were transfected with empty vector (Control) or plasmids expressing active JNK fusion proteins. 24 h following transfection, the cells were treated with 20 nM myostatin or Vehicle for 30 min. Cytosolic and nuclear fractions were collected and immunoblotting was performed to assess the localization of total and phosphorylated SMAD2 and JNK. d,e Nuclear accumulation of phosphorylated SMAD2 (SMAD2C) (d) and total SMAD2 (e) were quantified. Data are representative of three independent experiments (a, c) and the data displayed are replicates from one representative experiment. pSMAD2-C, C-terminus phosphorylated SMAD2; pJNK, phosphorylated (active) c-Jun N-terminal Kinase; pSMAD2L, linker-region phosphorylated SMAD2; SMAD2/3, total SMAD2/3; GAPDH is a cytosolic loading control; Lamin A/C is a nuclear loading control. Stain-free gel images (Bio-Rad) are also shown as a loading control (Loading). *P < 0.05, **P < 0.001, ***P < 0.0001 vs vehicle treatment by two-way ANOVA with Sidak’s post hoc testing. Main effects of genotype (JNK activity) are displayed. Bar plots indicate mean ± SEM for all dataCC BY · PubMed Central
Fig. 6 Lean mass and myogenic gene expression in mJNKKO mice. a, b Body weight was measured (a) and Lean mass (b) was calculated by DEXA in muscle-specific JNK1/2 knockout (mJNKKO) mice and wild-type (WT; MCK-Cre−/+) controls. N = 8 per group. c mRNA was extracted from the gastrocnemius muscle of WT and mJNKKO mice and expression levels of myogenic regulators and myostatin target genes were measured using RT-PCR. mRNA expression is expressed relative to β2-microglobulin housekeeping gene. Each data point represents the results from an individual animal. Bar plots indicate mean ± SEM for all data. P-values derived from unpaired t-tests are shown for each measurement. NS, not significant (P > 0.05)
Fig. 6 Lean mass and myogenic gene expression in mJNKKO mice. a, b Body weight was measured (a) and Lean mass (b) was calculated by DEXA in muscle-specific JNK1/2 knockout (mJNKKO) mice and wild-type (WT; MCK-Cre−/+) controls. N = 8 per group. c mRNA was extracted from the gastrocnemius muscle of WT and mJNKKO mice and expression levels of myogenic regulators and myostatin target genes were measured using RT-PCR. mRNA expression is expressed relative to β2-microglobulin housekeeping gene. Each data point represents the results from an individual animal. Bar plots indicate mean ± SEM for all data. P-values derived from unpaired t-tests are shown for each measurement. NS, not significant (P > 0.05)CC BY · PubMed Central
Fig. 7 SMAD2-linker phosphorylation with exercise humans. a Healthy young men underwent a standard session of endurance exercise (cycling; N = 8 per time point) or resistance exercise (weighted leg extension; N = 7 per time point). Skeletal muscle biopsies were taken before exercise (R; rest), immediately post-exercise (Time 0), and 15, 30, and 60 min post-exercise. b, c The time course of SMAD2-linker phosphorylation (pSMAD-L) (b) and JNK activation (pJNK) (c) was determined. Mean ± SEM are shown for (b) and (c). d Individual levels of pSMAD2-L in resting (Rest) and immediately post-exercise (Exercise) biopsies for each subject that underwent endurance exercise are shown with values from the same subject joined by a line. e Linear regression analysis identified a significant correlation between JNK phosphorylation and pSMAD2-linker phosphorylation. *P < 0.05 vs Rest by two-way ANOVA and Tukey’s Multiple Comparison Testing. pSMAD2L, linker-region phosphorylated SMAD2; pJNK, phosphorylated (active) C-Jun N-terminal Kinase. Different exposures are shown for the P54 and P46 splice forms of JNK, as the P54 band appeared darker in human skeletal muscle
Fig. 7 SMAD2-linker phosphorylation with exercise humans. a Healthy young men underwent a standard session of endurance exercise (cycling; N = 8 per time point) or resistance exercise (weighted leg extension; N = 7 per time point). Skeletal muscle biopsies were taken before exercise (R; rest), immediately post-exercise (Time 0), and 15, 30, and 60 min post-exercise. b, c The time course of SMAD2-linker phosphorylation (pSMAD-L) (b) and JNK activation (pJNK) (c) was determined. Mean ± SEM are shown for (b) and (c). d Individual levels of pSMAD2-L in resting (Rest) and immediately post-exercise (Exercise) biopsies for each subject that underwent endurance exercise are shown with values from the same subject joined by a line. e Linear regression analysis identified a significant correlation between JNK phosphorylation and pSMAD2-linker phosphorylation. *P < 0.05 vs Rest by two-way ANOVA and Tukey’s Multiple Comparison Testing. pSMAD2L, linker-region phosphorylated SMAD2; pJNK, phosphorylated (active) C-Jun N-terminal Kinase. Different exposures are shown for the P54 and P46 splice forms of JNK, as the P54 band appeared darker in human skeletal muscleCC BY · PubMed Central
Fig. 8 Hypothesized mechanisms by which JNK activation with exercise leads to muscle hypertrophy. Canonical myostatin signaling (depicted with black arrows) results in reduced myofiber size via receptor-mediated phosphorylation of SMAD2 on its C-terminus (Ser465/467). Myostatin-mediated SMAD2 phosphorylation induces dimerization with co-SMAD4 and translocation of the SMAD complex to the nucleus where DNA binding and transcription are initiated. Our data demonstrate that resistance exercise induces JNK activation and phosphorylation of SMAD2 in its linker region via a non-canonical pathway (depicted with red arrows). Phosphorylation of SMAD2 at specific linker region resides (Ser245/250/255) has an inhibitory effect on myostatin activity by preventing the nuclear translocation of SMAD2. Inhibition of myostatin via this novel JNK/SMAD pathway allows for exercise-induced muscle hypertrophy
Fig. 8 Hypothesized mechanisms by which JNK activation with exercise leads to muscle hypertrophy. Canonical myostatin signaling (depicted with black arrows) results in reduced myofiber size via receptor-mediated phosphorylation of SMAD2 on its C-terminus (Ser465/467). Myostatin-mediated SMAD2 phosphorylation induces dimerization with co-SMAD4 and translocation of the SMAD complex to the nucleus where DNA binding and transcription are initiated. Our data demonstrate that resistance exercise induces JNK activation and phosphorylation of SMAD2 in its linker region via a non-canonical pathway (depicted with red arrows). Phosphorylation of SMAD2 at specific linker region resides (Ser245/250/255) has an inhibitory effect on myostatin activity by preventing the nuclear translocation of SMAD2. Inhibition of myostatin via this novel JNK/SMAD pathway allows for exercise-induced muscle hypertrophyCC BY · PubMed Central

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Authors
Lessard, S. J., MacDonald, T. L., Pathak, P., Han, M. S., Coffey, V. G., Edge, J., Rivas, D. A., Hirshman, M. F., Davis, R. J., & Goodyear, L. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Joslin Diabetes Center (US)
  • University of Massachusetts Chan Medical School (US)
  • Bond University (AU)
  • Massey University (NZ)
  • Tufts University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Lessard, Sarah J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-08-02
Volume
9
Issue
1
Pages
3030-3030
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-05439-3
PMC
PMC6072737
OpenAlex
W2884155806
Cited by
119
References
57
Citations by year
2026: 10 · 2025: 14 · 2024: 16 · 2023: 14 · 2022: 17 · 2021: 14 · 2020: 21 · 2019: 12 · 2018: 1
FWCI
4.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship@UMassChan (submittedVersion, cc-by)
  • Bond University Research Portal (Bond University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • RMIT Research Repository (RMIT University Library) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
American Heart Association (15SDG25560057)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
c-Jun N-terminal kinase, skeletal muscle remodeling, myostatin, Smad2, resistance training, endurance exercise, muscle fiber growth, muscle oxidative capacity, cardiorespiratory fitness, mechanical stress, Smad2 phosphorylation, muscle mass
MeSH terms
Adult, Animals, Cell Nucleus, Enzyme Activation, Gene Expression Regulation, Humans, Hypertrophy, Mice, Inbred C57BL, Muscles, Phosphorylation, Physical Conditioning, Animal, Physical Endurance, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Integrases, Protein Transport, Muscle Development, JNK Mitogen-Activated Protein Kinases, Smad Proteins, Myostatin, HEK293 Cells

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