Physical training increases skeletal muscle Na⁺,K⁺-ATPase content (NKA) and improves exercise performance, but the effects of inactivity per se on NKA content and isoform abundance in human muscle are unknown. We investigated the effects of 23-day unilateral lower limb suspension (ULLS) and subsequent 4-wk resistance training (RT) on muscle function and NKA in 6 healthy adults, measuring quadriceps muscle peak torque; fatigue and venous [K⁺] during intense one-legged cycling exercise; and skeletal muscle NKA content ([³H]ouabain binding) and NKA isoform abundances (immunoblotting) in muscle homogenates (α_1-3, β_1-2) and in single fibers (α_1-3, β₁). In the unloaded leg after ULLS, quadriceps peak torque and cycling time to fatigue declined by 22 and 23%, respectively, which were restored with RT. Whole muscle NKA content and homogenate NKA α_1-3 and β_1-2 isoform abundances were unchanged with ULLS or RT. However, in single muscle fibers, NKA α₃ in type I (-66%, P = 0.006) and β₁ in type II fibers (-40%, P = 0.016) decreased after ULLS, with other NKA isoforms unchanged. After RT, NKA α₁ (79%, P = 0.004) and β₁ (35%, P = 0.01) increased in type II fibers, while α₂ (76%, P = 0.028) and α₃ (142%, P = 0.004) increased in type I fibers compared with post-ULLS. Despite considerably impaired muscle function and earlier fatigue onset, muscle NKA content and homogenate α₁ and α₂ abundances were unchanged, thus being resilient to inactivity induced by ULLS. Nonetheless, fiber type-specific downregulation with inactivity and upregulation with RT of several NKA isoforms indicate complex regulation of muscle NKA expression in humans.

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