Which is true about free calcium in the muscle cytoplasm?

• A. It can activate an important kinase called calmodulin-dependent kinase
• B. It activates mTOR directly
• C. It inhibits AMPK
• D. It reduces calcium release from the sarcoplasmic reticulum

Answer: (A)

Free calcium in the muscle cytoplasm serves as a signaling messenger. When Ca2+ levels rise, Ca2+ binds to calmodulin, forming a Ca2+-calmodulin complex that activates calmodulin-dependent kinases (CaMK). This CaMK signaling is a major way that the calcium signal drives metabolic and contractile responses in muscle, helping regulate processes like enzyme activity, substrate use, and gene expression in response to activity.

That makes the statement about activating a calmodulin-dependent kinase the best answer. CaMKs, especially CaMKII, are well-established targets of the Ca2+-calmodulin complex and play key roles in translating calcium signals into phosphorylation changes that adapt muscle function to exercise.

The other options don’t fit as direct effects of free cytosolic calcium. Calcium doesn’t directly activate mTOR; mTOR signaling is controlled primarily by nutrients and growth factors, with Ca2+-calmodulin signaling able to modulate pathways that touch mTOR but not act as a direct activator. Free calcium also does not inhibit AMPK; in fact, Ca2+-calmodulin–dependent pathways can activate AMPK via CaMKKβ, linking calcium signals to energy-sensing pathways. Finally, rising cytosolic Ca2+ does not reduce calcium release from the sarcoplasmic reticulum; rather, it participates in mechanisms that promote further calcium release (calcium-induced calcium release) to sustain contraction.