Alterations at the Cross-Bridge Level Are Associated with a Paradoxical Gain of Muscle Function In Vivo in a Mouse Model of Nemaline Myopathy

Nemaline myopathy is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. The first disease causing mutation (Met9Arg) was identified in the gene encoding α-tropomyosin_slow gene (TPM3). Considering the conflicting findings of the previous studies on the transgenic (Tg) mice carrying the TPM3^Met9Arg mutation, we investigated carefully the effect of the Met9Arg mutation in 8–9 month-old Tg(TPM3)^Met9Arg mice on muscle function using a multiscale methodological approach including skinned muscle fibers analysis and invivo investigations by magnetic resonance imaging and 31-phosphorus magnetic resonance spectroscopy. While invitro maximal force production was reduced in Tg(TPM3)^Met9Arg mice as compared to controls, invivo measurements revealed an improved mechanical performance in the transgenic mice as compared to the former. The reduced invitro muscle force might be related to alterations occuring at the cross-bridges level with muscle-specific underlying mechanisms. In vivo muscle improvement was not associated with any changes in either muscle volume or energy metabolism. Our findings indicate that TPM3(Met9Arg) mutation leads to a mild muscle weakness invitro related to an alteration at the cross-bridges level and a paradoxical gain of muscle function invivo. These results clearly point out that invitro alterations are muscle-dependent and do not necessarily translate into similar changes invivo.