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We investigated the mechanisms associated with E22K mutation in myosin regulatory light chain (RLC), found to cause hypertrophic cardiomyopathy (HCM) in humans and mice. Specifically, we characterized the mechanical profiles of papillary muscle fibers from transgenic mice expressing human ventricular RLC wild‐type (Tg‐WT) or E22K mutation (Tg‐E22K). Because the two mouse models expressed different amounts of transgene, the B6SJL mouse line (NTg) was used as an additional control. Mechanical experiments were carried out on Ca2+‐ and ATP‐activated fibers and in rigor. Sinusoidal analysis was performed to elucidate the effect of E22K on tension and stiffness during activation/rigor, tension‐pCa, and myosin cross‐bridge (CB) kinetics. We found significant reductions in active tension (by 54%) and stiffness (active by 40% and rigor by 54%). A decrease in the Ca2+ sensitivity of tension (by ∆pCa ~ 0.1) was observed in Tg‐E22K compared with Tg‐WT fibers. The apparent (=measured) rate constant of exponential process B (2πb: force generation step) was not affected by E22K, but the apparent rate constant of exponential process C (2πc: CB detachment step) was faster in Tg‐E22K compared with Tg‐WT fibers. Both 2πb and 2πc were smaller in NTg than in Tg‐WT fibers, suggesting a kinetic difference between the human and mouse RLC. Our results of E22K‐induced reduction in myofilament stiffness and tension suggest that the main effect of this mutation was to disturb the interaction of RLC with the myosin heavy chain and impose structural abnormalities in the lever arm of myosin CB. When placed in vivo, the E22K mutation is expected to result in reduced contractility and decreased cardiac output whereby leading to HCM. Sub‐Discipline Bioenergetics. Database The data that support the findings of this study are available from the corresponding authors upon reasonable request. Animal protocol BK20150353 (Soochow University). Research governance School of Nursing: Hua‐Gang Hu: seuboyh@163.com; Soochow University: Chen Ge chge@suda.edu.cn.