Physical inactivity–gene interactions result in changes in gene expression, leading to phenotypic changes in the skeletal muscle cell. A subpopulation of those genes that show changes in expression during physical inactivity are candidates for the environment–gene interactions that cross a threshold of biological significance such that overt clinical disease occurs. AMP kinase, GLUT4 and myosin heavy chain IIx are proposed as candidates for physical inactivity-modulated genes that have an altered function that may trigger a crossing of a threshold to disease. Future experiments will be needed to test the validity of the ideas presented.