1. Isometric and isotonic contractile parameters of the soleus (SOL) and medial gastrocnemius (MG) muscles of seven adult cats were studied. In addition, architectural characteristics of six contralateral pairs of these ankle extensors were determined. 2. The in situ peak isometric tetanic tension developed by the MG at the Achilles tendon is nearly 5 times (9,846 vs 2,125 g) that of the SOL muscle. However, when differences between the MG and SOL in fiber length (2.01 vs 3.66 cm), muscle mass (9.80 vs. 3.31 g), and angle of pinnation (21.4 vs. 6.4 degrees) are considered, the specific tensions of these muscles are similar (approximately 2.3 kg x cm-2). 3. When the effects of muscle architecture are eliminated, the nearly threefold greater maximum isotonic shortening velocity (Vmax) of sarcomeres of the MG (38.2 micron/s) relative to the SOL (13.4 micron/s) is presumably due to intrinsic differences in the biochemical properties of these muscle. However, the Vmax developed by the MG at the Achilles tendon (258.6 mm/s) during a shortening contraction is only 1.5 times that of the SOL (176.3 mm/s) due to the influence of these muscles' specific architectures. 4. Variations in geometrical characteristics of the SOL and MG are consonant with the relative amounts of participation of these muscles during posture, locomotion, and jumping. Posture requires the development of low forces for prolonged periods for which the SOL seems best suited both architecturally and physiologically. The MG, relatively inactive during quiet standing, becomes responsible for a greater percentage of tension and shortening speed during plantar flexion (E3) as gait speeds increase, which is consistent with this muscle's greater tension- and velocity-generating capacity. 5. At high speeds of locomotion (3.0 m/s) and jumping, the shortening velocities developed at the end of E3 (approximately 20-40 ms before paw off) exceed Vmax of the SOL. Consequently, the SOL, although electrically active, cannot contribute to the tensions required to generate the shortening velocities dictated by these movements. 6. These data demonstrate the influence of the differing geometries of the SOL and MG on the roles of these muscles in generating forces at varying velocities, as demanded by the dynamics of the movement.

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Contractile and histochemical properties of rat soleus muscle were studied bilaterally after 2 or 4 weeks of denervation (DEN), which eliminates activity and non-activity-related influences, and chronic application of tetrodotoxin (TTX) to the motor nerve, which produces a completely inactive innervated muscle. After 2 or 4 weeks of disuse, the percentages of slow twitch oxidative fibers in both DEN-and TTX-treated soleus were reduced significantly and to similar extents. The dynamic contractile properties of TTX-treated and denervated muscles were similar to those of control muscle after 2 weeks, but by 4 weeks, parallel increases were seen in normalized rate of tension development and maximal shortening speed of these muscles.

Morphological, contractile, and histochemical properties of rat soleus muscle were studied after 2 or 4 weeks of complete elimination of neuromuscular activity. Inactivity was induced by chronic perfusion of tetrodotoxin (TTX) to the sciatic nerve. Significant reductions in muscle mass and fiber size were found after 2 or 4 weeks of disuse. Correspondingly, the percentage of dark-staining alkaline myosin ATPase fibers was increased from about 20% to 40% after 4 weeks of treatment. The capacity of soleus to generate tension when stimulated through the nerve was significantly impaired at frequencies greater than 20 Hz. Nevertheless, when the curarized muscle was stimulated directly, tension developed at frequencies above 20 Hz relative to peak tension was similar to control values. Absolute tetanic tension was significantly reduced after 2 or 4 weeks of treatment. These reductions could be only partly explained by muscle atrophy, resulting in specific tensions or approximately 55% of control after 2 or 4 weeks of treatment. Measures of the time course of the isometric twitch were found not to be reliable indicators of the contractile speed in TTX-treated soleus. Significant increases in the rate of tetanic tension development, expressed relative to peak tension, and the velocity of unloaded shortening, were seen after 4 weeks of disuse. These results reveal the extent to which virtually complete neuromuscular inactivity leads to chronic deficits in neuromuscular transmission and changes in both the net amount and quality of contractile proteins of rat soleus muscle.

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SUMMARY1. This report describes selected histochemical and physiological properties of the motor units of adult cat soleus muscle approximately one year after self-and cross-reinnervation with the nerve of the heterogenous flexor hallucis longus (f.h.l.). Self-reinnervated f.h.l. motor units are also considered. Whole muscles were tested for fibre reaction to alkaline pre-incubated ATPase, cz-glycerophosphate dehydrogenase (a-GPD) and reduced nicotinamide adenine dinucleotide diaphorase (NADH-D). Motor units were isolated and studied by splitting the ventral root in acute preparations.2. The histochemical fibre type profile in the self-reinnervated muscle was comparable to normal muscle as was mean twitch contraction time, twitch-tetanus ratio and fatigue index. The mean tetanic tension of the soleus self-and cross-reinnervated motor units appeared close to a normal soleus whereas the mean tetanic tension of the f.h.l. self-reinnervated units was significantly less than a normal f.h.l.3. An average of 14 % of the fibres of the soleus cross-reinnervated muscles had high ATPase and a c-GPD staining intensity in contrast to normal and selfreinnervated soleus in which such fibres are absent. Thus alkaline lability of myofibrillar ATPase increased in some fibres of what was originally a homogeneous population. The small increase in the number of densely staining fibres for ATPase at an alkaline pH (14 %) was associated with a 73 % decrease in (mean) contraction time (41 + 11 ms) of the thirty-three cross-reinnervated muscle units studied, with no unit's contraction time greater than 60 ms. Mean contraction times for the self-reinnervated soleus and f.h.l. muscles were 78 + 31 ms and 27 + 8 ms respectively.4. All fibres of the soleus cross-reinnervated muscles showed intense reaction to NADH-D, as was true of self-reinnervated soleus. This staining pattern is typical of normal soleus. In concordance, these motor units consistently demonstrated a high resistance to fatigue when stimulated for a four-minute period.5. These results suggest that in the adult self-and cross-reinnervated soleus muscle,

The original experiment of Buller et al. and the many subsequent confirmatory reports clearly show that the time-to-peak tension and many other speed-related parameters of slow and fast muscle fibres are dictated by the motoneurone. It has been concluded that the motoneurone exerts this control of the physiological and associated biochemical properties by the frequency at which it excites the muscle fibre. However, no studies have been reported on the fatigue properties and the associated biochemical characteristics after cross-reinnervation. Based on the 'size principle' of motoneurones, it would be reasonable to assume that a muscle fibre reinnervated by a small motoneurone would be active often and that this would be manifested biochemically as an elevated oxidative capacity. Also, it has been shown repeatedly that the mitochondrial content of a muscle fibre can be modified by daily endurance type exercise. Thus, it would seem that the motoneurone at least indirectly also controls the mitochondrial content of a muscle fibre by controlling the degree of activity. We have now tested this hypothesis using self- and cross-reinnervated muscles in cats. We found that fast- and slow-twitch muscles retained their characteristic fatigue resistance properties regardless of whether the nerve to which they had become connected had originally innervated a fatigue-resistant or relatively fatiguable muscle.

patients and after treatment initiation for nusinersen-treated patients. Results: A total of 349 SMA1 patients (median age=1 year; 55.6% female) with median follow-up of 7.9 months were included. The proportion of patients receiving mechanical ventilation, nutritional support, and physical therapy/rehabilitation was 46.4%, 46.1%, and 22.6%. Patients had, on average, 59.4 days with medical visits/year (14.1 inpatient, 13.4 respiratory failure-related). The 45 nusinersentreated patients had, on average, 56.6 days with medical visits/year (4.6 inpatient, 11.4 respiratory failure-related). Excluding nusinersenrelated costs, mean healthcare costs PPPY were $137,627 (median: $43,167) for all patients and $92,618 ($29,425) for nusinersen-treated patients. Mean nusinersen-related costs were $191,909 ($144,487) per month for the first 3 months post-initiation and $36,882 ($16,132) per month thereafter. Conclusions: HRU and costs associated with SMA1 are substantial, even among patients treated with nusinersen.Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2-25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.