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 preincubation
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