Muscle disuse leads to a considerable loss in skeletal muscle mass and strength. However, the cellular mechanisms underlying disuse-induced muscle fibre atrophy remain to be elucidated. Therefore we assessed the effect of muscle disuse on the CSA (cross-sectional area), muscle fibre size, satellite cell content and associated myocellular signalling pathways of the quadriceps muscle. A total of 12 healthy young (24±1 years of age) men were subjected to 2 weeks of one-legged knee immobilization via a full-leg cast. Before and immediately after the immobilization period and after 6 weeks of natural rehabilitation, muscle strength [1RM (one-repetition maximum)], muscle CSA [single slice CT (computed tomography) scan] and muscle fibre type characteristics (muscle biopsies) were assessed. Protein and/or mRNA expression of key genes [i.e. MYOD (myogenic differentiation), MYOG (myogenin) and MSTN (myostatin)] in the satellite cell regulatory pathways were determined using Western blotting and RT-PCR (real-time PCR) analyses respectively. The present study found that quadriceps CSA declined following immobilization by 8±2% (P<0.05). In agreement, both type I and type II muscle fibre size decreased 7±3% and 13±4% respectively (P<0.05). No changes were observed in satellite cell content following immobilization in either type I or type II muscle fibres. Muscle MYOG mRNA expression doubled (P<0.05), whereas MSTN protein expression decreased 30±9% (P<0.05) following immobilization. Muscle mass and strength returned to the baseline values within 6 weeks of recovery without any specific rehabilitative programme. In conclusion, 2 weeks of muscle disuse leads to considerable loss in skeletal muscle mass and strength. The loss in muscle mass was attributed to both type I and type II muscle fibre atrophy, and was not accompanied by a decline in satellite cell content.