Matrix produced by diseased cardiac fibroblasts affects early myotube formation and function

Janny Piñeiro-Llanes, Silveli Suzuki-Hatano, Ananya Jain, Valerie A. Pérez Medina, William Todd Cade, Christina A. Pacak, Chelsey S. Simmons

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The extracellular matrix (ECM) provides both physical and chemical cues that dictate cell function and contribute to muscle maintenance. Muscle cells require efficient mitochondria to satisfy their high energy demand, however, the role the ECM plays in moderating mitochondrial function is not clear. We hypothesized that the ECM produced by stromal cells with mitochondrial dysfunction (Barth syndrome, BTHS) provides cues that contribute to metabolic dysfunction independent of muscle cell health. To test this, we harnessed the ECM production capabilities of human pluripotent stem-cell-derived cardiac fibroblasts (hPSC-CFs) from healthy and BTHS patients to fabricate cell-derived matrices (CDMs) with controlled topography, though we found that matrix composition from healthy versus diseased cells influenced myotube formation independent of alignment cues. To further investigate the effects of matrix composition, we then examined the influence of healthy- and BTHS-derived CDMs on myotube formation and metabolic function. We found that BTHS CDMs induced lower fusion index, lower ATP production, lower mitochondrial membrane potential, and higher ROS generation than the healthy CDMs. These findings imply that BTHS-derived ECM alone contributes to myocyte dysfunction in otherwise healthy cells. Finally, to investigate potential mechanisms, we defined the composition of CDMs produced by hPSC-CFs from healthy and BTHS patients using mass spectrometry and identified 15 ECM and related proteins that were differentially expressed in the BTHS-CDM compared to healthy CDM. Our results highlight that ECM composition affects skeletal muscle formation and metabolic efficiency in otherwise healthy cells, and our methods to generate patient-specific CDMs are a useful tool to investigate the influence of the ECM on disease progression and to investigate variability among diseased patients. Statement of significance: Muscle function requires both efficient metabolism to generate force and structured extracellular matrix (ECM) to transmit force, and we sought to examine the interactions between metabolism and ECM when metabolic disease is present. We fabricated patient-specific cell derived matrices (CDMs) with controlled topographic features to replicate the composition of healthy and mitochondrial-diseased (Barth syndrome) ECM. We found that disease-derived ECM negatively affects metabolic function of otherwise healthy myoblasts, and we identified several proteins in disease-derived ECM that may be mediating this dysfunction. We anticipate that our patient-specific CDM system could be fabricated with other topographies and cell types to study cell functions and diseases of interest beyond mitochondrial dysfunction and, eventually, be applied toward personalized medicine.

Original languageEnglish (US)
Pages (from-to)100-112
Number of pages13
JournalActa Biomaterialia
Volume152
DOIs
StatePublished - Oct 15 2022

Bibliographical note

Funding Information:
The authors acknowledge the support by the National Institute of Health [ 5R01 HL 136759-5 , S10 OD021758-01A1 ] and the National Science Foundation [ EEC 1757128 ]. We thank Dr. Kari Basso for her technical assistance with the LC-MS/MS analysis and Dr. Bryan James and Taiye (Thomas) Zhang for their technical assistance with the Bio-AFM. We also thank Paul Smaglik for his editorial assistance preparing the manuscript.

Publisher Copyright:
© 2022 Acta Materialia Inc.

Keywords

  • Barth syndrome
  • Cell-derived matrices
  • Extracellular matrix
  • Mitochondria
  • Myogenesis
  • Tissue engineering

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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