The loss of strength and function following prolonged unweighting may result from alterations in skeletal muscle and/or neurological properties. In this paper (Part I) we report our findings on plantarflexor muscle properties following 4-weeks of unilateral lower limb suspension (ULLS), along with the efficacy of applied ischemia (ISC) on these properties. In the companion paper (Part II) we report our findings on the changes in neurological properties and the effectiveness of a novel intervention (motor imagery), along with collectively analyzing our findings from both papers to determine the relative contribution of neural and muscular factors in strength loss. In the present study, measurements of voluntary and stimulated forces, the compound muscle fiber action potential (CMAP) and muscle cross-sectional area (CSA, via MRI) were collected before and after 4-weeks of ULLS in healthy adults (n=18; 19-28 years). A subset of subjects (n=6) received applications of ischemia (ISC) 3 days per week (3-sets; 5-min duration). In the subjects not receiving the ISC, the loss in muscle mass and strength was as expected (~ 9 & 14%). We observed a 30% slowing in the duration of the CMAP, a 10% decrease in evoked doublet force, a 12% increase in evoked twitch-to-doublet force ratio, and an altered post-activation potentiation (PAP) force response (11% increase in the PAP-to-doublet ratio). We also detected a 10% slowing in the ability of the muscle to develop force during the initial phase of an evoked contraction, along with a 6% reduction in in vivo specific doublet force (doublet force/CSA). In the subjects receiving ISC, no preservation was observed in strength, nor did it alter the ULLS-induced response in evoked muscle properties. However, the ISC group did preferentially maintain CSA of the lateral gastrocnemius (LG) muscle compared to the ULLS control group, as the LG of the subjects not receiving an intervention atrophied 10.2% while the subjects receiving ISC atrophied 4.7%. Additionally, ISC abolished the unweighting-induced slowing in the CMAP. These findings suggest that unweighting alters the contractile properties involved in the excitation-contraction coupling processes, and that ISC impacts the sarcolemma.