SMN deficiency induces an early non-atrophic myopathy with alterations in the contractile and excitatory coupling machinery of skeletal myofibers in the SMN{triangleup}7 mouse model of spinal muscular atrophy

Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMN{Delta}7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN{Delta}7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. Focal and segmental lesions in the myofibrillar contractile apparatus were noticed in myofibers. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation-contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the view of an intrinsic alteration of skeletal muscle in SMA, suggesting that this peripheral tissue is a key therapeutic target for the disease. Graphical summarySchematic representation of the main cellular and ultrastructural changes occurring in tibialis anterior (TA) myofibers of the SMN{Delta}7 mouse model of severe SMA during the pre-neurodegenerative stage (PND, P0-P7). See that the PND stage is characterized by the absence of MN loss and muscular atrophy but, SMN deficient myofibers display multiple alterations. Observe the early impact of low SMN levels on sarcoplasmic reticulum and triads, myofibril contractile cytoskeleton, and intermyofibrillar mitochondria. Notice that all alterations are associated with a specific myonuclear domain. Changes in mRNA levels of different genes involved in myogenesis and mitochondrial biogenesis are also shown compared to age-matched WT animals. Figure created with BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/612470v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@17ae050org.highwire.dtl.DTLVardef@1cd31borg.highwire.dtl.DTLVardef@67c2e9org.highwire.dtl.DTLVardef@2d5141_HPS_FORMAT_FIGEXP M_FIG C_FIG