Animals have different muscle fibre types: slow fibres with a low maximum velocity of shortening (Vmax) and fast fibres with a high Vmax. An advantage conferred by the use of different fibre types during locomotion has been proposed solely on the basis of their in vitro properties. Isolated muscle experiments show that force generation, mechanical power production and efficiency are all functions of V/Vmax, where V is the velocity of muscle shortening. But it is not known whether animals actually use the different fibres at shortening velocities that are optimal for mechanical power production and efficiency. Here we compare the V of muscle fibres during locomotion with their Vmax. This comparison shows that during slow locomotion, the slow fibres shorten at a velocity that gives peak mechanical power and efficiency and the fast fibres shorten at their optimal velocity when powering maximal movements. Our results also show that maximal movements are impossible without fast fibres because the slow ones cannot shorten rapidly enough.

Frogs must generate a high level of mechanical power when they jump. The muscular system of frogs that jump is presumably designed to deliver these high powers. The length changes and activation pattern that muscles undergo during jumping were measured, and isolated muscle bundles were driven through this in vivo pattern. During jumping, muscles generated maximum power. Specifically, the muscle fibers (i) operated at optimal sarcomere lengths, (ii) operated at optimal shortening velocities, and (iii) were maximally activated during power generation. Thus, many different parameters must have evolved in concert to produce a system capable of this explosive jumping movement.

Spinal muscular atrophy (SMA) is caused by homozygous mutation or deletion of the SMN1 gene encoding survival of motor neuron (SMN) protein, resulting in the selective loss of ␣-motor neurons. Humans typically have one or more copies of the SMN2 gene, the coding region of which is nearly identical to SMN1, except that a point mutation causes splicing out of exon 7 and production of a largely nonfunctional SMN⌬7 protein. The development of drugs that mitigate aberrant SMN2 splicing is an attractive therapeutic approach for SMA. A steric block antisense oligonucleotide (AO) has recently been developed that blocked an intronic splice suppressor element, and enhanced SMN2 exon 7 inclusion in SMA patient fibroblasts. Here, we show that periodic intracerebroventricular (ICV) delivery of this AO resulted in increased SMN expression in brain and spinal cord to as much as 50% of the level of healthy littermates. Real-time PCR of SMN2 transcripts confirmed the AO-mediated increase in full-length SMN. The AO-derived increase in SMN expression led to a concomitant improvement in bodyweight throughout the lifespan of the SMA animals. Treatment of SMA mice with AO also provided partial correction of motor deficits, manifest as improved righting response. Injections of a scrambled oligonucleotide had no effect on SMN expression or phenotype in the SMA mice. Our results validate that AOs that abrogate aberrant splicing of SMN2 are promising compounds for treating SMA.

siRNA and antisense oligonucleotides, AON, have similar size and negative charge and are often packaged for in vitro delivery with cationic lipids or polymers–but exposed positive charge is problematic in vivo. Here we demonstrate loading and functional delivery of RNAi and AON with non-ionic, nano-transforming polymersomes. These degradable carriers are taken up passively by cultured cells after which the vesicles transform into micelles that allow endolysosomal escape and delivery of either siRNA into cytosol for mRNA knockdown or else AON into the nucleus for exon skipping within pre-mRNA. Polymersome-mediated knockdown appears as efficient as common cationic-lipid transfection and about half as effective as Lentivirus after sustained selection. For AON, initial results also show that intramuscular injection into a mouse model of muscular dystrophy leads to the expected protein expression, which occurs along the entire length of muscle. The lack of cationic groups in antisense polymersomes together with initial tests of efficacy suggests broader utility of these non-viral carriers.