Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia

Rosa Vono, Claudia Fuoco, Stefano Testa, Stefano Pirró, Davide Maselli, David Ferland McCollough, Elena Sangalli, Gianfranco Pintus, Roberta Giordo, Giovanna Finzi, Fausto Sessa, Rosanna Cardani, Ambra Gotti, Sergio Losa, Gianni Cesareni, Roberto Rizzi, Claudia Bearzi, Stefano Cannata, Gaia Spinetti, Cesare Gargioli & 1 others Paolo Madeddu

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Critical limb ischemia (CLI), foot ulcers, former amputation, and impaired regeneration are independent risk factors for limb amputation in subjects with diabetes. The present work investigates whether and by which mechanism diabetes negatively impacts on functional properties of muscular pericytes (MPs), which are resident stem cells committed to reparative angiomyogenesis. We obtained muscle biopsy samples from patients with diabetes who were undergoing major limb amputation and control subjects. Diabetic muscles collected at the rim of normal tissue surrounding the plane of dissection showed myofiber degeneration, fat deposition, and reduction of MP vascular coverage. Diabetic MPs (D-MPs) display ultrastructural alterations, a differentiation bias toward adipogenesis at the detriment of myogenesis and an inhibitory activity on angiogenesis. Furthermore, they have an imbalanced redox state, with downregulation of the antioxidant enzymes superoxide dismutase 1 and catalase, and activation of the pro-oxidant protein kinase C isoform β-II (PKCβII)- dependent p66Shc signaling pathway. A reactive oxygen species scavenger or, even more effectively, clinically approved PKCβII inhibitors restore D-MP angiomyogenic activity. Inhibition of the PKCβII-dependent p66Shc signaling pathway could represent a novel therapeutic approach for the promotion of muscle repair in individuals with diabetes.

Original languageEnglish
Pages (from-to)3691-3704
Number of pages14
JournalDiabetes
Volume65
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

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Pericytes
Amputation
Protein Kinase C
Reactive Oxygen Species
Protein Isoforms
Skeletal Muscle
Ischemia
Extremities
Muscles
Foot Ulcer
Adipogenesis
Muscle Development
Catalase
Oxidation-Reduction
Blood Vessels
Dissection
Regeneration
Stem Cells
Down-Regulation
Antioxidants

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia. / Vono, Rosa; Fuoco, Claudia; Testa, Stefano; Pirró, Stefano; Maselli, Davide; McCollough, David Ferland; Sangalli, Elena; Pintus, Gianfranco; Giordo, Roberta; Finzi, Giovanna; Sessa, Fausto; Cardani, Rosanna; Gotti, Ambra; Losa, Sergio; Cesareni, Gianni; Rizzi, Roberto; Bearzi, Claudia; Cannata, Stefano; Spinetti, Gaia; Gargioli, Cesare; Madeddu, Paolo.

In: Diabetes, Vol. 65, No. 12, 01.12.2016, p. 3691-3704.

Research output: Contribution to journalArticle

Vono, R, Fuoco, C, Testa, S, Pirró, S, Maselli, D, McCollough, DF, Sangalli, E, Pintus, G, Giordo, R, Finzi, G, Sessa, F, Cardani, R, Gotti, A, Losa, S, Cesareni, G, Rizzi, R, Bearzi, C, Cannata, S, Spinetti, G, Gargioli, C & Madeddu, P 2016, 'Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia', Diabetes, vol. 65, no. 12, pp. 3691-3704. https://doi.org/10.2337/db16-0248
Vono, Rosa ; Fuoco, Claudia ; Testa, Stefano ; Pirró, Stefano ; Maselli, Davide ; McCollough, David Ferland ; Sangalli, Elena ; Pintus, Gianfranco ; Giordo, Roberta ; Finzi, Giovanna ; Sessa, Fausto ; Cardani, Rosanna ; Gotti, Ambra ; Losa, Sergio ; Cesareni, Gianni ; Rizzi, Roberto ; Bearzi, Claudia ; Cannata, Stefano ; Spinetti, Gaia ; Gargioli, Cesare ; Madeddu, Paolo. / Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia. In: Diabetes. 2016 ; Vol. 65, No. 12. pp. 3691-3704.
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abstract = "Critical limb ischemia (CLI), foot ulcers, former amputation, and impaired regeneration are independent risk factors for limb amputation in subjects with diabetes. The present work investigates whether and by which mechanism diabetes negatively impacts on functional properties of muscular pericytes (MPs), which are resident stem cells committed to reparative angiomyogenesis. We obtained muscle biopsy samples from patients with diabetes who were undergoing major limb amputation and control subjects. Diabetic muscles collected at the rim of normal tissue surrounding the plane of dissection showed myofiber degeneration, fat deposition, and reduction of MP vascular coverage. Diabetic MPs (D-MPs) display ultrastructural alterations, a differentiation bias toward adipogenesis at the detriment of myogenesis and an inhibitory activity on angiogenesis. Furthermore, they have an imbalanced redox state, with downregulation of the antioxidant enzymes superoxide dismutase 1 and catalase, and activation of the pro-oxidant protein kinase C isoform β-II (PKCβII)- dependent p66Shc signaling pathway. A reactive oxygen species scavenger or, even more effectively, clinically approved PKCβII inhibitors restore D-MP angiomyogenic activity. Inhibition of the PKCβII-dependent p66Shc signaling pathway could represent a novel therapeutic approach for the promotion of muscle repair in individuals with diabetes.",
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