AbstractAimXin is an F‐actin‐binding protein expressed during development of cardiac and skeletal muscle. We used Xin‐/‐ mice to determine the impact of Xin deficiency on different aspects of skeletal muscle health, including functionality and regeneration.MethodsXin‐/‐ skeletal muscles and their satellite cell (SC) population were investigated for the presence of myopathic changes by a series of histological and immunofluorescent stains on resting uninjured muscles. To further understand the effect of Xin loss on muscle health and its SCs, we studied SCs responses following cardiotoxin‐induced muscle injury. Functional data were determined using in situ muscle stimulation protocol.ResultsCompared to age‐matched wild‐type (WT), Xin‐/‐ muscles exhibited generalized myopathy and increased fatigability with a significantly decreased force recovery post‐fatiguing contractions. Muscle regeneration was attenuated in Xin‐/‐ mice. This impaired regeneration prompted an investigation into SC content and functionality. Although SC content was not different, significantly more activated SCs were present in Xin‐/‐ vs. WT muscles. Primary Xin‐/‐ myoblasts displayed significant reductions (approx. 50%) in proliferative capacity vs. WT; a finding corroborated by significantly decreased MyoD‐positive nuclei in 3 days post‐injury Xin‐/‐ muscle vs. WT. As more activated SCs did not translate to more proliferating myoblasts, we investigated whether Xin‐/‐ SCs displayed an exaggerated loss by apoptosis. More apoptotic SCs (TUNEL+/Pax7+) were present in Xin‐/‐ muscle vs. WT. Furthermore, more Xin‐/‐ myoblasts were expressing nuclear caspase‐3 compared to WT at 3 days post‐injury.ConclusionXin deficiency leads to a myopathic condition characterized by increased muscle fatigability, impaired regeneration and SC dysfunction.
