title: Metformin protects skeletal muscle from cardiotoxin induced degeneration.
abstract: The skeletal muscle tissue has a remarkable capacity to regenerate upon injury. Recent studies have suggested that this regenerative process is improved when AMPK is activated. In the muscle of young and old mice a low calorie diet, which activates AMPK, markedly enhances muscle regeneration. Remarkably, intraperitoneal injection of AICAR, an AMPK agonist, improves the structural integrity of muscles of dystrophin-deficient mdx mice. Building on these observations we asked whether metformin, a powerful anti-hyperglycemic drug, which indirectly activates AMPK, affects the response of skeletal muscle to damage. In our conditions, metformin treatment did not significantly influence muscle regeneration. On the other hand we observed that the muscles of metformin treated mice are more resilient to cardiotoxin injury displaying lesser muscle damage. Accordingly myotubes, originated in vitro from differentiated C2C12 myoblast cell line, become more resistant to cardiotoxin damage after pre-incubation with metformin. Our results indicate that metformin limits cardiotoxin damage by protecting myotubes from necrosis. Although the details of the molecular mechanisms underlying the protective effect remain to be elucidated, we report a correlation between the ability of metformin to promote resistance to damage and its capacity to counteract the increment of intracellular calcium levels induced by cardiotoxin treatment. Since increased cytoplasmic calcium concentrations characterize additional muscle pathological conditions, including dystrophies, metformin treatment could prove a valuable strategy to ameliorate the conditions of patients affected by dystrophies.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Langone
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cannata
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fuoco
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Lettieri Barbato
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Testa
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Aurelio Pio
authors.initials: AP
authors.lastname: Nardozza
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Ciriolo
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Castagnoli
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gargioli
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy; Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Cesareni
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D031204:Caloric Restriction; D002460:Cell Line; D026901:Membrane Transport Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018482:Muscle, Skeletal / Q000502:physiology*; D009336:Necrosis / Q000139:chemically induced / Q000188:drug therapy; D011956:Receptors, Cell Surface / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*
chemical_list: D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011956:Receptors, Cell Surface; C489997:Tomm20 protein, mouse; D008687:Metformin; D002118:Calcium