Adenosine and its derivatives may induce acute changes, i.e., injury and death, in muscle cells. In the present work, we evaluated the intracellular calcium concentration in C2C12 myogenic cells differentiated in vitro to form myotubes and exposed to a metabolically stable analogue of adenosine, g-chloro-adenosine. The compound was able to significantly modify ionic homeostasis by sensitizing muscle cells to the excitatory amino acid glutamate. A single exposure to glutamate led to a marked increase in intracellular calcium level. This is the first demonstration that adenosine analogues can regulate muscle cell integrity and function via an indirect increase of intracellular calcium ions.