(A) In healthy muscle, Ca²⁺ release occurs in a coordinated fashion during contraction, and [Ca²⁺]_cyt is low at rest. Organelles (e.g., the nucleus and mitochondria) sense changes in [Ca²⁺]_cyt, which regulates cellular functions including transcription and energy metabolism. (B) Stress-induced PKA-mediated phosphorylation of RyR1 alters the way skeletal muscle handles Ca²⁺ during contraction and relaxation. PKA hyperphosphorylation of RyR1, resulting in calstabin1 depletion from the channel complex, leads to an SR Ca²⁺ leak in the resting muscle, potentially influencing nuclear and mitochondrial function. Ca²⁺ leak also decreases SR load, and less Ca²⁺ is available for release during contraction. β-AR, β-adrenergic receptor.