CaV1.1 is a voltage gated calcium channel exclusively expressed in the skeletal muscle where its primary function is to sense changes in membrane potential thereby activating the ryanodine receptor 1 through physical interaction resulting in calcium release from the sarcoplasmic reticulum. This leads to the excitation-coupled contraction of the skeletal muscle. CaV1.1e is a newly discovered embryonic splice variant of this L-type calcium channel. Apart from its function as a voltage sensor in excitation-contraction (E-C) coupling, and in contrast to the adult CaV1.1a variant, it also supports sizeable calcium currents activating at the physiological membrane potential. Splicing defects resulting in elevated expression levels of the CaV1.1e variant in mature muscle have been shown to correlate with the degree of muscle weakness in patients suffering from dystrophic myotonia. In order to study the physiological importance of the developmental switch from a well conducting to a poorly conducting channel and to examine its putative involvement in dystrophic muscle weakness, we generated a mouse model (CaV1.1E29) in which exon 29 of the Cacna1s gene is permanently deleted. Quantitative RT-PCR analysis demonstrates that CaV1.1E29 mice express exclusively the CaV1.1e splice variant at levels comparable to total CaV1.1 in wildtype muscle; although western blot analysis showed a 20-40% reduction of CaV1.1 protein in specific muscle types. A battery of behavioral tests (home-cage activity, voluntary and forced running, grip strength and rotarod tests) revealed reduced muscle strength but otherwise normal motor performance compared to wildtype siblings. Combined voltage clamp and fluorescence calcium recordings of isolated muscle fibers from CaV1.1E29 mice revealed a substantial influx-dependent component of the calcium transient which is not present in controls. Furthermore the function of store refilling upon calcium depletion was overtaken by CaV1.1e in CaV1.1E29 mice compared to STIM/ORAI1 driven store-operated calcium entry (SOCE) in wildtype mice. Immunofluorescence analysis of myosin heavy chain isoforms revealed a shift in the fiber type composition to slower fiber types in both slow (soleus) and fast (EDL) muscle of CaV1.1E29 mice. Consistent with the shift towards slow fiber types, experiments on isolated whole soleus and EDL muscles showed decreased amplitude of twitch and tetanic force, altered force frequency relationship and increased fatigue resistance in both soleus and EDL muscles in the CaV1.1E29 mice. However, inconsistent with the fiber type shift, histological staining for succinate dehydrogenase activity showed a reduction in oxidative metabolism in knockout soleus and EDL muscles. Further analysis of both slow and fast muscles with transmission electron microscopy revealed increased percentage of damaged mitochondria in both soleus and EDL muscles of CaV1.1E29 mice with no visible damage to myofibrils and E-C coupling membranes. This indicates that the increased calcium influx not only interferes with the signaling cascade for fiber type regulation but also causes calcium overload in the muscles thereby causing oxidative damage. The reduced muscle strength and mitochondrial damage could be the beginning of the muscle weakness and damage observed in myotonic dystrophy. Together these findings clearly suggest that the perinatal down-regulation of L-type calcium currents is important not only for the regulation and maintenance of the specific fiber type composition in skeletal muscles but also to maintain calcium homeostasis and prevent muscle weakness and damage.