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 language | English |
|---|---|
| Pages (from-to) | 3691-3704 |
| Number of pages | 14 |
| Journal | Diabetes |
| Volume | 65 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 1 2016 |
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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 journal › Article
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TY - JOUR
T1 - Activation of the pro-oxidant PKCβIIp66Shc Signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb Ischemia
AU - Vono, Rosa
AU - Fuoco, Claudia
AU - Testa, Stefano
AU - Pirró, Stefano
AU - Maselli, Davide
AU - McCollough, David Ferland
AU - Sangalli, Elena
AU - Pintus, Gianfranco
AU - Giordo, Roberta
AU - Finzi, Giovanna
AU - Sessa, Fausto
AU - Cardani, Rosanna
AU - Gotti, Ambra
AU - Losa, Sergio
AU - Cesareni, Gianni
AU - Rizzi, Roberto
AU - Bearzi, Claudia
AU - Cannata, Stefano
AU - Spinetti, Gaia
AU - Gargioli, Cesare
AU - Madeddu, Paolo
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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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U2 - 10.2337/db16-0248
DO - 10.2337/db16-0248
M3 - Article
VL - 65
SP - 3691
EP - 3704
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -