Research ArticleGeneticsMuscle biology Open Access | 10.1172/jci.insight.181946

Philip K. Farahat,1,2,3 Chino Kumagai-Cresse,4 Raquel L. Aragón,4,5 Feiyang Ma,4 Justin K. Amakor,4 Alejandro Espinoza,6 Irina Kramerova,4 Robert J. Jimenez,4,5 Bradley M. Smith,4 Jesus Perez,4 Rachelle H. Crosbie,4,5,7 Apoorva H. Nagendra,1,2,3 Jackie McCourt-Towner,7 Gerald Coulis,1,2,3 Oluwatayo F. Ikotun,5,8,9,14 April D. Pyle,5,10,9 Matteo Pellegrini,11 Elizabeth M. McNally,12 S. Armando Villalta,1,2,3,13 and Melissa J. Spencer4,5,9,14

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Farahat, P. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Kumagai-Cresse, C. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Aragón, R. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Ma, F. in: PubMed | Google Scholar |

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Amakor, J. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Espinoza, A. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Kramerova, I. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Jimenez, R. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Smith, B. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Perez, J. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Crosbie, R. in: PubMed | Google Scholar |

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Nagendra, A. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by McCourt-Towner, J. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Coulis, G. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Ikotun, O. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Pyle, A. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Pellegrini, M. in: PubMed | Google Scholar |

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by McNally, E. in: PubMed | Google Scholar

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Villalta, S. in: PubMed | Google Scholar |

1Department of Physiology and Biophysics,

2Muscle Biology and Disease Research Center, and

3Institute for Immunology, University of California, Irvine, California, USA.

4Department of Neurology,

5Molecular Biology Institute,

6Department of Human Genetics,

7Department of Integrative Biology and Physiology,

8Department of Molecular and Medical Pharmacology,

9Eli and Edyth Broad Stem Cell Center,

10Department of Microbiology, Immunology and Molecular Genetics, and

11Department of Molecular, Cellular and Developmental Biology,UCLA, Los Angeles, California, USA.

12Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, USA.

13Department of Neurology, University of California, Irvine, California, USA.

14Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.

Address correspondence to: S. Armando Villalta, University of California, Irvine 3036 Hewitt Hall, Mail Code: 4560, Irvine, California, 92697, USA. Phone: 949.824.6150; Email: armando.villalta@uci.edu. Or to: Melissa J. Spencer, Neuroscience Research Building 635 Charles Young Dr. South. Los Angeles, California, 90095, USA. Phone: 310.794.5225; Email: MSpencer@mednet.ucla.edu.

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Find articles by Spencer, M. in: PubMed | Google Scholar

Authorship note: PKF, CKC, and RLA have been designated as co-first authors. SAV and MJS are co-senior authors.

Published July 8, 2025 - More info

Published in Volume 10, Issue 13 on July 8, 2025
JCI Insight. 2025;10(13):e181946. https://doi.org/10.1172/jci.insight.181946.
© 2025 Farahat et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published July 8, 2025 - Version history
Received: April 10, 2024; Accepted: May 28, 2025 View PDF Abstract

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder involving cycles of muscle degeneration and regeneration, leading to accumulation of intramuscular fibrosis and fat. Ablation of Osteopontin/Spp1 in a murine model of DMD (mdx) improves the dystrophic phenotype, but the source of Spp1 and its impact on target cells in dystrophic muscles remain unknown. In dystrophic muscles, macrophages are the predominate infiltrating leukocyte and express high levels of Spp1. We used macrophage-specific ablation combined with single-cell transcriptional profiling to uncover the impact of macrophage-derived Spp1 on cell-cell interactions in mdx muscles. Ablation of macrophage-specific Spp1 (cKO) correlated with reduction of 2 PDGFRa+ stromal cell populations, expressing Lifr+ and Procr+. Sorting and transcriptional profiling of these populations confirmed that they are enriched in adipogenesis genes and are highly related to fibroadipogenic precursors (FAPS). These adipogenic stromal cells (ASC) displayed more adipogenic potential in vitro compared with FAPS, likely due to a more differentiated state. Reduction of ASCs correlated with reduced intramuscular diaphragmatic fat and improved diaphragm function. These data suggest a role for myeloid-derived Spp1 in the differentiation of stromal cells towards an adipogenic fate, leading to accumulation of intramuscular fat in dystrophic muscles.

Graphical Abstract Introduction

Duchenne muscular dystrophy (DMD) is one of the most common inherited, lethal childhood diseases. This X-linked recessive disorder is caused by mutations in the DMD gene encoding dystrophin (1), an important sarcolemmal membrane protein that protects myofibers from contraction-induced injury (2–4). The lack of functional dystrophin in DMD leads to chronic cycles of muscle degeneration and regeneration and accumulation of TGFb (5).

In acute muscle injury, healthy muscle repair follows a carefully orchestrated process that is initiated by infiltration of neutrophils and then Ly6chi, F4/80lo monocytes to the damaged area (6–8). These monocytes differentiate from a proinflammatory M1 phenotype towards a proregenerative macrophage phenotype (Ly6clo, F4/80hi) (8–11). Progression from a proinflammatory microenvironment, induced by M1-like macrophages, to a proreparative microenvironment, induced by M2-like macrophages, is crucial for regulating stromal cell extracellular matrix secretion and growth factors that support regeneration (12, 13). This phenotypic switch is accompanied by acute activation and expansion of stromal cells, including fibroadipogenic progenitor cells (FAPs) and fibroblasts, which lay down the connective tissue that provides structural support for the damaged site (13). Infiltrating myeloid cells are also essential for activation of muscle stem cells (MuSC) that regenerate myofibers (12, 14, 15). The microenvironment established by this precisely regulated inflammatory and stromal cell response is crucial for proper muscle regeneration.

In the setting of chronic damage and repair, such as in DMD muscles, a dysregulated inflammatory response leads to the prolonged presence of both proinflammatory and proregenerative macrophages and accumulation of the profibrotic cytokine, TGF-β (5, 16). While evidence of M1 and M2 macrophage activation has been documented in dystrophic muscle (8, 9) more recent studies have challenged the view that the M1 and M2 paradigm accurately reflects the molecular phenotype and function of dystrophic muscle macrophages. Single-cell transcriptomic studies showed that skeletal muscle resident macrophages and recruited monocytes acquire a molecular signature characterized by high expression of Lgals3, Spp1, Trem2, Gpnmb, and Cd9, none of which are classic markers of M1 or M2 activation (11). This dysregulated macrophage state, combined with profibrotic signaling through TGF-β, hinders muscle regeneration while promoting muscle fibrosis and accumulation of intramuscular adipose tissue (IMAT) (17–19). The source of IMAT has been previously attributed to FAPS (12–14).

We previously identified osteopontin (Spp1) as a modifier of TGF-β1 expression that promotes dystrophic disease in mdx muscle (6, 8, 20, 21). Spp1 is a ubiquitously expressed, matricellular protein that is highly upregulated in dystrophic muscle (6). Global knockout of Spp1 in mdx mice led to an improved dystrophic phenotype, including increased muscle function, increased muscle regeneration, reduced proinflammatory (M1) muscle macrophages, reduced TGF-β1 expression, and reduced collagen deposition, compared with Spp1-sufficient mdx mice (6, 8, 20, 21).

Spp1 is a ubiquitously expressed protein that can be secreted or reside intracellularly. It is involved in a diverse array of biological processes and signaling pathways. In the extracellular matrix, Spp1 engages multiple cell surface receptors such as integrins, CD44, and components of the ECM such as heparin (22, 23). In the dystrophic niche, Spp1 is expressed by a variety of cell types, including immune cells, stromal cells, muscle fibers, endothelial cells, and muscle stem cells (24). Importantly, Spp1 is posttranslationally modified by phosphorylation, glycosylation, and transglutamination and is cleaved by thrombin and metalloproteases. Thus, depending on the cellular source of Spp1, its posttranslational modifications, and the proximity of receptors, the effects on target cells can vary. However, the influence of cell-specific Spp1 on different target cells within the highly dynamic dystrophic niche remains poorly understood.

Here, we generated myeloid-specific conditional knockouts of Spp1 (cKO) and used scRNA-seq to