Abstract
The phosphodiesterases inhibitor pentoxifylline gained attention for Duchenne muscular dystrophy therapy for its claimed anti-inflammatory, antioxidant, and antifibrotic action. A recent finding also showed that pentoxifylline counteracts the abnormal overactivity of a voltage-independent calcium channel in myofibers of dystrophic mdx mice. The possible link between workload, altered calcium homeostasis, and oxidative stress pushed toward a more detailed investigation. Thus a 4- to 8-wk treatment with pentoxifylline (50 mg·kg-1·day-1 ip) was performed in mdx mice, undergoing or not a chronic exercise on treadmill. In vivo, the treatment partially increased forelimb strength and enhanced resistance to treadmill running in exercised animals. Ex vivo, pentoxifylline restored the mechanical threshold, an electrophysiological index of calcium homeostasis, and reduced resting cytosolic calcium in extensor digitorum longus muscle fibers. Mn quenching and patch-clamp technique confirmed that this effect was paralleled by a drug-induced reduction of membrane permeability to calcium. The treatment also significantly enhanced isometric tetanic tension in mdx diaphragm. The plasma levels of creatine kinase and reactive oxygen species were both significantly reduced in treated-exercised animals. Dihydroethidium staining, used as an indicator of reactive oxygen species production, showed that pentoxifylline significantly reduced the exercise-induced increase in fluorescence in the mdx tibialis anterior muscle. A significant decrease in connective tissue area and profibrotic cytokine transforming growth factor-β1 was solely found in tibialis anterior muscle. In both diaphragm and gastrocnemius muscle, a significant increase in neural cell adhesion molecule-positive area was instead observed. This data supports the interest toward pentoxifylline and allows insight in the level of cross talk between pathogenetic events in workloaded dystrophic muscle.
| Original language | English |
|---|---|
| Pages (from-to) | 1311-1324 |
| Number of pages | 14 |
| Journal | Journal of Applied Physiology |
| Volume | 106 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2009 |
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Keywords
- Calcium homeostasis
- Exercise
- Muscular dystrophy
- Oxidative stress
- Phosphodiesterase inhibitors
- Preclinical test
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
Cite this
Multiple pathological events in exercised dystrophic mdx mice are targeted by pentoxifylline : Outcome of a large array of in vivo and ex vivo tests. / Burdi, Rosa; Rolland, Jean François; Fraysse, Bodvael; Litvinova, Karina; Cozzoli, Anna; Giannuzzi, Viviana; Liantonio, Antonella; Camerino, Giulia Maria; Sblendorio, Valeriana; Capogrosso, Roberta Francesca; Palmieri, Beniamino; Andreetta, Francesca; Confalonieri, Paolo; De Benedictis, Leonarda; Montagnani, Monica; De Luca, Annamaria.
In: Journal of Applied Physiology, Vol. 106, No. 4, 04.2009, p. 1311-1324.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Multiple pathological events in exercised dystrophic mdx mice are targeted by pentoxifylline
T2 - Outcome of a large array of in vivo and ex vivo tests
AU - Burdi, Rosa
AU - Rolland, Jean François
AU - Fraysse, Bodvael
AU - Litvinova, Karina
AU - Cozzoli, Anna
AU - Giannuzzi, Viviana
AU - Liantonio, Antonella
AU - Camerino, Giulia Maria
AU - Sblendorio, Valeriana
AU - Capogrosso, Roberta Francesca
AU - Palmieri, Beniamino
AU - Andreetta, Francesca
AU - Confalonieri, Paolo
AU - De Benedictis, Leonarda
AU - Montagnani, Monica
AU - De Luca, Annamaria
PY - 2009/4
Y1 - 2009/4
N2 - The phosphodiesterases inhibitor pentoxifylline gained attention for Duchenne muscular dystrophy therapy for its claimed anti-inflammatory, antioxidant, and antifibrotic action. A recent finding also showed that pentoxifylline counteracts the abnormal overactivity of a voltage-independent calcium channel in myofibers of dystrophic mdx mice. The possible link between workload, altered calcium homeostasis, and oxidative stress pushed toward a more detailed investigation. Thus a 4- to 8-wk treatment with pentoxifylline (50 mg·kg-1·day-1 ip) was performed in mdx mice, undergoing or not a chronic exercise on treadmill. In vivo, the treatment partially increased forelimb strength and enhanced resistance to treadmill running in exercised animals. Ex vivo, pentoxifylline restored the mechanical threshold, an electrophysiological index of calcium homeostasis, and reduced resting cytosolic calcium in extensor digitorum longus muscle fibers. Mn quenching and patch-clamp technique confirmed that this effect was paralleled by a drug-induced reduction of membrane permeability to calcium. The treatment also significantly enhanced isometric tetanic tension in mdx diaphragm. The plasma levels of creatine kinase and reactive oxygen species were both significantly reduced in treated-exercised animals. Dihydroethidium staining, used as an indicator of reactive oxygen species production, showed that pentoxifylline significantly reduced the exercise-induced increase in fluorescence in the mdx tibialis anterior muscle. A significant decrease in connective tissue area and profibrotic cytokine transforming growth factor-β1 was solely found in tibialis anterior muscle. In both diaphragm and gastrocnemius muscle, a significant increase in neural cell adhesion molecule-positive area was instead observed. This data supports the interest toward pentoxifylline and allows insight in the level of cross talk between pathogenetic events in workloaded dystrophic muscle.
AB - The phosphodiesterases inhibitor pentoxifylline gained attention for Duchenne muscular dystrophy therapy for its claimed anti-inflammatory, antioxidant, and antifibrotic action. A recent finding also showed that pentoxifylline counteracts the abnormal overactivity of a voltage-independent calcium channel in myofibers of dystrophic mdx mice. The possible link between workload, altered calcium homeostasis, and oxidative stress pushed toward a more detailed investigation. Thus a 4- to 8-wk treatment with pentoxifylline (50 mg·kg-1·day-1 ip) was performed in mdx mice, undergoing or not a chronic exercise on treadmill. In vivo, the treatment partially increased forelimb strength and enhanced resistance to treadmill running in exercised animals. Ex vivo, pentoxifylline restored the mechanical threshold, an electrophysiological index of calcium homeostasis, and reduced resting cytosolic calcium in extensor digitorum longus muscle fibers. Mn quenching and patch-clamp technique confirmed that this effect was paralleled by a drug-induced reduction of membrane permeability to calcium. The treatment also significantly enhanced isometric tetanic tension in mdx diaphragm. The plasma levels of creatine kinase and reactive oxygen species were both significantly reduced in treated-exercised animals. Dihydroethidium staining, used as an indicator of reactive oxygen species production, showed that pentoxifylline significantly reduced the exercise-induced increase in fluorescence in the mdx tibialis anterior muscle. A significant decrease in connective tissue area and profibrotic cytokine transforming growth factor-β1 was solely found in tibialis anterior muscle. In both diaphragm and gastrocnemius muscle, a significant increase in neural cell adhesion molecule-positive area was instead observed. This data supports the interest toward pentoxifylline and allows insight in the level of cross talk between pathogenetic events in workloaded dystrophic muscle.
KW - Calcium homeostasis
KW - Exercise
KW - Muscular dystrophy
KW - Oxidative stress
KW - Phosphodiesterase inhibitors
KW - Preclinical test
UR - http://www.scopus.com/inward/record.url?scp=66149144404&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66149144404&partnerID=8YFLogxK
U2 - 10.1152/japplphysiol.90985.2008
DO - 10.1152/japplphysiol.90985.2008
M3 - Article
C2 - 19131478
AN - SCOPUS:66149144404
VL - 106
SP - 1311
EP - 1324
JO - Journal of Applied Physiology
JF - Journal of Applied Physiology
SN - 8750-7587
IS - 4
ER -