Injury to the central nervous system (CNS) generally results in significant neuronal death and functional loss. In vitro experiments have demonstrated that neurotrophic factors such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and neurotrophin-4/5 (NT-4/5) can promote neuronal survival. However, delivery to the injured CNS is difficult as these large protein molecules do not efficiently cross the blood–brain barrier. Intranasal delivery of 70 μg [¹²⁵I]-radiolabeled BDNF, CNTF, NT-4, or erythropoietin (EPO) resulted in 0.1–1.0 nM neurotrophin concentrations within 25 min in brain parenchyma. In addition, not only did these neurotrophic factors reach the CNS, they were present in sufficient concentrations to activate the prosurvival PI3Kinase/Akt pathway, even where lower levels of neurotrophic factors were measured. Currently traumatic, ischemic and compressive injuries to the CNS have no effective treatment. There is potential clinical relevancy of this method for rescuing injured CNS tissues in order to maintain CNS function in affected patients. The intranasal delivery method has great clinical potential due to (1) simplicity of administration, (2) noninvasive drug administration, (3) relatively rapid CNS delivery, (4) ability to repeat dosing easily, (5) no requirement for drug modification, and (6) minimal systemic exposure.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.

Purpose. Mammalian extraocular muscles (EOMs) are both physiologically and biochemically unique when compared with nonocular skeletal muscles. Recent studies have demonstrated a process of continuous myonuclear addition in normal uninjured myofibers in adult EOMs of rabbits and mice. The current study was conducted to determine whether this process of myonuclear addition is a universal phenomenon in mammalian EOMs. methods. The EOMs from adult uninjured monkeys and humans were examined immunohistochemically for the expression of specific markers of activated satellite cells: hepatocyte growth factor (HGF); the myogenic regulatory factors MyoD, myogenin, and Pax7; and a marker for nuclei in all proliferative phases of the cell cycle, Ki-67. The satellite cell identity of the cells positive for Ki-67, HGF, and Pax7 was determined by colabeling sets of serial sections with either laminin or dystrophin. results. In cross sections of monkey and human EOMs, approximately 7% to 8% of the myofiber profiles were associated with Pax7-positive satellite cells and between 2% and 4% were associated with MyoD-positive satellite cells or HGF-positive satellite cells. Similar percentages of satellite cells were positive for myogenin in the orbital layer, but the global layer had few satellite cells that were myogenin positive. An average of 0.72% of the myofibers had Ki-67–positive cells associated with them in the satellite cell position. conclusions. Activated satellite cells were present on myofibers in normal uninjured adult monkey and human EOMs, as visualized with these five distinct markers. The data support the hypothesis that the process of continuous myonuclear addition is most likely active in primate and human EOMs. The presence of continuous myofiber remodeling in EOM suggests new mechanisms that may be responsible for EOM sparing or involvement in skeletal muscle diseases.

Quantification of key outcome measures in animal models of aging is an important step preceding intervention testing. One such measurement, skeletal muscle power generation (force * velocity), is critical for dynamic movement. Prior research focused on maximum power (P _max), which occurs around 30–40 % of maximum load. However, movement occurs over the entire load range. Thus, the primary purpose of this study was to determine the effect of age on power generation during concentric contractions in the extensor digitorum longus (EDL) and soleus muscles over the load range from 10 to 90 % of peak isometric tetanic force (P ₀). Adult, old, and elderly male C57BL/6 mice were examined for contractile function (6–7 months old, 100 % survival; ~24 months, 75 %; and ~28 months, 50 % P ₀). The shape of the force-velocity curve also changed with age (a/P ₀ increased). In addition, there were prolonged contraction times to maximum force and shifts in the distribution of the myosin light and heavy chain isoforms in the EDL. The results demonstrate that age-associated difficulty in movement during challenging tasks is likely due, in addition to overall reduced force output, to an accelerated deterioration of power production and contractile velocity under heavily loaded conditions.

The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin −/− ( dko ) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin +/− mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin +/− mice for long‐term DMD studies, limb muscle pathology and function were assessed across the life span of wild‐type, mdx , mdx:utrophin +/− , and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin +/− mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin +/− mice compared to mdx mice at 12 months. Mdx:utrophin +/− mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin +/− muscle compared to mdx at most ages examined. Generally, mdx:utrophin +/− mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin +/− mice may be a more useful animal model than mdx or dko mice for investigating long‐term efficacy of potential treatments when fibrosis or muscle function is the focus.

Purpose. Botulinum toxin A (Botox) is commonly used for strabismus treatment. Although other muscles atrophy after intramuscular injection with Botox, extraocular muscles (EOMs) do not. A continuous process of myonuclear addition in normal uninjured adult myofibers in rabbit EOMs was studied. In this study, the effect of Botox-induced muscle paralysis on myofiber remodeling in adult EOMs was examined. methods. The superior rectus muscles of adult rabbits were each injected with 5 units of Botox. The contralateral muscle received injections of saline only. Bromodeoxyuridine (BrdU) was administered for various periods after Botox treatment, followed by various BrdU-free periods. Myonuclear addition, the number of BrdU-positive satellite cells, and the number of MyoD-positive satellite cells were quantified, as were alterations in expression of immature myosins. results. Intramuscular injection of Botox resulted in a significant increase in both the number of BrdU-positive myonuclei and satellite cells. MyoD expression in both satellite cells and myonuclei was significantly increased after Botox injection in EOMs. In Botox-treated EOMs, an increased number of myofibers positive for the neonatal myosin heavy chain (MyHC) isoform was detected in the orbital layer. conclusions. Botox-induced EOM paralysis resulted in a significant short-term increase in satellite cell activation and myonuclear addition in single myofibers in adult rabbit EOMs compared with control muscles. The appearance of MyoD-positive myonuclei suggests that protein synthesis becomes upregulated after Botox injection, and this, in turn, may help explain the minimal effects on myofiber size in EOMs after Botox injection. Understanding the effect of Botox on satellite cell activation and myonuclear addition in existing myofibers may suggest new ways to maximize the clinical effectiveness of Botox in patients with strabismus.