Tibialis anterior muscles in mdx mice are highly susceptible to contraction-induced injury

Skeletal muscles of patients with Duchenne muscular dystrophy (DMD) and mdx mice lack dystrophin and are more susceptible to contraction-induced injury than control muscles. Our purpose was to develop an assay based on the high susceptibility to injury of limb muscles in mdx mice for use in evaluating therapeutic interventions. The assay involved two stretches of maximally activated tibialis anterior (TA) muscles in situ . Stretches of 40% strain relative to muscle fiber length were initiated from the plateau of isometric contractions. The magnitude of damage was assessed one minute later by the deficit in isometric force. At all ages (2–19 months), force deficits were four- to seven-fold higher for muscles in mdx compared with control mice. For control muscles, force deficits were unrelated to age, whereas force deficits increased dramatically for muscles in mdx mice after 8 months of age. The increase in susceptibility to injury of muscles from older mdx mice did not parallel similar adverse effects on muscle mass or force production. The in situ stretch protocol of TA muscles provides a valuable assay for investigations of the mechanisms of injury in dystrophic muscle and to test therapeutic interventions for reversing DMD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43148/1/10974_2004_Article_390575.pd

Functional evaluation of the reversibility of muscular dystrophy in the <italic>mdx</italic> mouse via dystrophin restoration.

Duchenne muscular dystrophy (DMD), a degenerative, lethal muscle disorder and the most common form of MD, is caused by mutations in the dystrophin gene. Transgenic and adenoviral vector technologies have demonstrated the feasibility of gene therapy for DMD by the restoration of dystrophin and subsequent prevention of the development of dystrophy in skeletal muscles of the dystrophin-deficient mdx mouse, a model of DMD. However, the ability to halt and reverse muscle deterioration once the disease has progressed remains unclear. The primary goal of this research was to examine the potential for reversal of functional deficiencies in the mdx mouse. Muscles of mdx mice lack dystrophin and as a result are more susceptible to contraction-induced damage than muscles from control mice. An in situ assay that reveals the high susceptibility to injury of dystrophic limb muscles was developed and utilized to characterize the extent of muscle damage in mdx and control mice at different ages. In an attempt to reduce the susceptibility to injury, the restoration of full-length dystrophin to muscles of adult mdx mice was achieved by delivery with gutted adenoviral vectors that are devoid of all viral genes. High level expression of dystrophin corrected the susceptibility to contraction-induced injury in muscles of mdx mice by 40%. These studies demonstrated (1) the ability of adenoviral vectors to transduce muscles of adult, immunocompetent, mdx mice and (2) that expression of virally-delivered full-length dystrophin partially reverses the major pathophysiological abnormality of dystrophic muscle. The results from this research will help further the development of gene therapy for muscular dystrophy.Ph.D.Animal PhysiologyBiological SciencesMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/129366/2/3042062.pd

Force–EMG Changes During Sustained Contractions of a Human Upper Airway Muscle

Human upper airway and facial muscles support breathing, swallowing, speech, mastication, and facial expression, but their endurance performance in sustained contractions is poorly understood. The muscular fatigue typically associated with task failure during sustained contractions has both central and intramuscular causes, with the contribution of each believed to be task dependent. Previously we failed to show central fatigue in the nasal dilator muscles of subjects that performed intermittent maximal voluntary contractions (MVCs). Here we test the hypothesis that central mechanisms contribute to the fatigue of submaximal, sustained contractions in nasal dilator muscles. Nasal dilator muscle force and EMG activities were recorded in 11 subjects that performed submaximal contractions (20, 35, and 65% MVC) until force dropped to ≤90% of the target force for ≥3 s, which we defined as task failure. MVC and twitch forces (the latter obtained by applying supramaximal shocks to the facial nerve) were recorded before the trial and at several time points over the first 10 min of recovery. The time to task failure was inversely related to contraction intensity. MVC force was depressed by roughly 30% at task failure in all three trials, but recovered within 2 min. Twitch force fell by 30–44% depending on contraction intensity and remained depressed after 10 min of recovery, consistent with low-frequency fatigue. Average EMG activity increased with time, but never exceeded 75% of the maximal, pretrial level despite task failure. EMG mean power frequency declined by 20–25% in all trials, suggesting reduced action potential conduction velocity at task failure. In contrast, the maximal evoked potential did not change significantly in any of the tasks, indicating that the EMG deficit at task failure was due largely to mechanisms proximal to the neuromuscular junction. Additional experiments using the interpolated twitch technique suggest that subjects can produce about 92% of the maximal evocable force with this muscle, which is not a large enough deficit to explain the entire shortfall in the EMG at task failure. These data show that the nervous system fails to fully activate the nasal dilator muscles during sustained, submaximal contractions; putative mechanisms are discussed

In vivo acceleration of heart relaxation performance by parvalbumin gene delivery

Defective cardiac muscle relaxation plays a causal role in heart failure. Shown here is the new in vivo application of parvalbumin, a calcium-binding protein that facilitates ultrafast relaxation of specialized skeletal muscles. Parvalbumin is not naturally expressed in the heart. We show that parvalbumin gene transfer to the heart in vivo produces levels of parvalbumin characteristic of fast skeletal muscles, causes a physiologically relevant acceleration of heart relaxation performance in normal hearts, and enhances relaxation performance in an animal model of slowed cardiac muscle relaxation. Parvalbumin may offer the unique potential to correct defective relaxation in energetically compromised failing hearts because the relaxation-enhancement effect of parvalbumin arises from an ATP-independent mechanism. Additionally, parvalbumin gene transfer may provide a new therapeutic approach to correct cellular disturbances in calcium signaling pathways that cause abnormal growth or damage in the heart or other organs