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.
Highlights
Dietary restriction without malnutrition is proven to extend a healthy average life span by delaying the onset of multiple age-associated diseases in a variety of organisms including primates [1]
For the cardiotoxin muscle-crush injury mice were anesthetized with an intramuscular injection of physiologic saline (10 ml/Kg) containing ketamine (5 mg/ml) and xylazine (1 mg/ml) and 10 mM of cardiotoxin isolated from Naja pallida (Latoxan L81-02) were intramuscularly administered into the tibialis anterior (TA) and gastrocnemius (GC) muscle
To study the consequences of metabolic alterations induced by metformin treatment on skeletal muscle damage and regeneration, C57BL/6 mice were treated with a daily intraperitoneal injections of saline solution of metformin (200 mg/kg body weight) or of PBS as control for 21 days
Summary
Dietary restriction without malnutrition is proven to extend a healthy average life span by delaying the onset of multiple age-associated diseases in a variety of organisms including primates [1]. Cerletti and colleagues reported evidence that calorie restriction (CR) helps to maintain stem cell function in aging muscles [4] They observed that mitochondrial abundance and oxygen consumption increased in satellite cells (SCs) from mice on calorie-restricted diet. This metabolic perturbation was associated with an increase in SCs transplant efficiency. Jahnke and collaborators demonstrated that intraperitoneal injections of AICAR (an AMPK agonist) improve the structural integrity and reduce the degeneration/regeneration of dystrophin-deficient mdx mouse muscle. This effect was ascribed to an increase in oxidative metabolism in the AICAR treated muscle fibers [5]
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