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Muscle biology. Clinical considerations.

Recent advances in muscle biology have greatly expanded our knowledge of how muscle functions in health and disease and how muscle adapts to a variety of stimuli. The purpose of this review is to consider how this information can be applied to the practice of physical therapy. The opinions and ideas represent those of a clinician who is also involved in research on the functional performance of muscle and how performance relates to basic biological mechanisms. The review examines selected aspects of muscle physiology, muscle mutability, and problems that arise when basic research material must be generalized for clinical practice.

Adenosine Triphosphate↗

Role of extracellular matrix and its regulators in human airway smooth muscle biology.

Altered extracellular matrix (ECM) deposition contributing to airway wall remodeling is an important feature of asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanisms of this process are poorly understood. One of the key pathological features of these diseases is thickening of airway walls. This thickening is largely to the result of airway smooth muscle (ASM) cell hyperplasia and hypertrophy as well as increased deposition of ECM proteins such as collagens, elastin, laminin, and proteoglycans around the smooth muscle. Many growth factors and cytokines, including fibroblast growth factor (FGF)-1, FGF-2, and transforming growth factor (TGF)-beta1, that are released from the airway wall have the potential to contribute to airway remodeling, revealed by enhanced ASM proliferation and increased ECM protein deposition. TGF-beta1 and FGF-1 stimulate mRNA expression of collagen I and III in ASM cells, suggesting their role in the deposition of extracellular matrix proteins by ASM cells in the airways of patients with chronic lung diseases. Focus is now on the bidirectional relationship between ASM cells and the ECM. In addition to increased synthesis of ECM proteins, ASM cells can be involved in downregulation of matrix metalloproteinases (MMPs) and upregulation of tissue inhibitors of metalloproteinases (TIMPs), thus eventually contributing to the alteration in ECM. In turn, ECM proteins promote the survival, proliferation, cytokine synthesis, migration, and contraction of human airway smooth muscle cells. Thus, the intertwined relationship of ASM and ECM and their response to stimuli such as chronic inflammation in diseases such as asthma and COPD contribute to the remodeling seen in airways of patients with these diseases.

Cell Movement↗

Experimentally induced defects of mitochondrial metabolism in rat skeletal muscle. Biological effects of the mitochondrial uncoupling agent 2,4-dinitrophenol.

Infusion of dinitrophenol intra-arterially into rat hind limb caused an irreversible failure of isometric twitch tension and the induction of a severe progressive contracture. Metabolite analysis of muscle in which the twitch response had grossly fatigued revealed low levels of ATP and phosphocreatine together with lactate accumulation. Studies using 31P-n.m.r. confirmed the decrease in ATP and creatine phosphate concentrations and indicated a fall in intracellular pH. It is concluded that dinitrophenol-induced myopathy does not represent a good model for the human mitochondrial myopathic condition as has been previously suggested.

2,4-Dinitrophenol↗

Experimentally induced defects of mitochondrial metabolism in rat skeletal muscle. Biological effects of the NADH: coenzyme Q reductase inhibitor diphenyleneiodonium.

An animal model for the human condition of mitochondrial myopathy has been established and characterized physiologically and biochemically. The NADH: coenzyme Q reductase inhibitor diphenyleneiodonium [Bloxham (1979) Biochem. Soc. Trans. 7, 103-106] was either infused acutely in vivo into rat hind limb or injected chronically into rats. Both modes of delivery resulted in a reduced muscle oxidative capacity and increased fatigue. Analysis of muscle metabolites by h.p.l.c. and 31P-n.m.r. indicated that ATP concentrations were similar to control values during periods of stimulation and these were maintained by the phosphocreatine pool. During the recovery period after muscle stimulation in the experimental animals the muscle pH remained depressed and the rate of phosphocreatine synthesis was markedly delayed as compared with controls. Factors thought to be involved in the fatigue response are discussed in relation to this model.

Animals↗

Evidence for a resident subset of cells with SP phenotype in the C2C12 myogenic line: a tool to explore muscle stem cell biology.

Muscle satellite cells are heterogeneous and present functional disparities, some of them behaving as multipotent stem cells. Yet their phenotype is obscure and their isolation remains elusive. The ability to purify stem cells from a wide variety of tissues by using Hoechst 33342 staining/FACS methods has permitted access to this category of cells (side population, or SP) in a manner independent of antibodies. Here, we show that the C2C12 myogenic line comprises a minor population of cells with SP phenotype. These cells are growth-arrested and delayed in their ability to differentiate. Dye efflux in C2C12-derived SPs is likely mediated by mdr1a, whose overexpression results in increased dedifferentiation. Interestingly, growth-arrested SPs rapidly appear in purified MP populations, thus suggesting a dynamic equilibrium among different states of differentiation. Finally, transcriptional profiling of C2C12-derived SP and MP cells corroborates the many similarities of SP to stem cells.

ATP Binding Cassette Transporter, Subfamily B↗

Muscle injuries: biology and treatment.

Muscle injuries are one of the most common traumas occurring in sports. Despite their clinical importance, few clinical studies exist on the treatment of these traumas. Thus, the current treatment principles of muscle injuries have either been derived from experimental studies or been tested only empirically. Although nonoperative treatment results in good functional outcomes in the majority of athletes with muscle injuries, the consequences of failed treatment can be very dramatic, possibly postponing an athlete's return to sports for weeks or even months. Moreover, the recognition of some basic principles of skeletal muscle regeneration and healing processes can considerably help in both avoiding the imminent dangers and accelerating the return to competition. Accordingly, in this review, the authors have summarized the prevailing understanding on the biology of muscle regeneration. Furthermore, they have reviewed the existing data on the different treatment modalities (such as medication, therapeutic ultrasound, physical therapy) thought to influence the healing of injured skeletal muscle. In the end, they extend these findings to clinical practice in an attempt to propose an evidence-based approach for the diagnosis and optimal treatment of skeletal muscle injuries.

Athletic Injuries↗

Action of biologically active peptides on monkey iris sphincter and dilator muscles.

Biologically active peptides modulate pupillary responsiveness in many non-primate mammals. We examined the action of seven different peptides on iris sphincter and dilator muscles of rhesus monkey. Iris sphincter and dilator muscle preparations from rhesus monkeys were mounted in an organ bath, and tension changes were recorded by an isometric transducer. Electrical field stimulation (100Hz, 0.3 msec, 10V) was applied through a pair of platinum plate electrodes. Monkey iris sphincter and dilator muscles produced simple cholinergic and adrenergic excitatory responses respectively to electrical field stimulation. Strong field stimulation did not elicit slow Substance P (SP) mediated contractions like those in rabbit iris sphincter. Exogenously applied pituitary adenylate cyclase-activating peptide (PACAP) enhanced in a concentration-dependent manner (0.3 nM-0.1 microm) the sphincter response to field stimulation, while neuropeptide Y (NPY) and somatostatin (SRIF) attenuated it. These three peptides did not affect sphincter contractions induced by acetylcholine, and therefore were acting at presynaptically. SP, calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and galanin (GAL) had no effect (at 0.1 microm) on iris sphincter. None of seven exogenously applied peptides had an effect on monkey iris dilator muscle. The innervation of primate irises may be relatively simple compared to non-primates because each of the peptides in this study can modulate miosis or mydriasis in non-primate mammals. Future studies will be expected on the functional significance of species differences in iridial innervation.

Acetylcholine↗

Metal content of shark muscle powder biological reference material.

Powdered dried shark muscle (Cephaloscyllium umbratile) is a promising biological reference material for metal analysis. Homogeneity indices (CV%) for Na, K, Zn, As, Ca, and Hg of the shark powder were within 5%. Mercury and arsenic concentrations (total Hg, 9.1 ppm dry wt, As, 99 ppm dry wt) in shark powder are relatively high. Muscle can be obtained inexpensively, and the powder can be preserved indefinitely if kept cold.

Animals↗

Experimental development of an electrically stimulated biological skeletal muscle ventricle for chronic aortic counterpulsation.

OBJECTIVE: The chronic shortage of donor organs for cardiac transplantation and the high costs for mechanical assist devices demand the development of alternative cardiac assist devices for the treatment of severe heart failure. Cardiac assistance by stimulated skeletal muscles is currently investigated as such a possible alternative. The goal of the presented study was to construct a newly designed biological skeletal muscle ventricle and to evaluate its possible hemodynamic efficacy in an acute sheep model. METHODS: A total of 14 adult sheep were used for acute experiments. The entire thoracic aorta including the aortic root was excised from a donor sheep. An aorto-pericardial pouch conduit (APPC) was created by enlarging the aortic circumference in its middle section with two strips of pericardium. This biological conduit was anastomosed in parallel to the descending aorta of a recipient sheep, using the aortic root as an inflow valve to the conduit. Stimulation electrodes were applicated to the thoracodorsal nerve and the latissimus dorsi muscle was detached from the trunk and wrapped around the pouch. ECG-triggered functional electrical stimulation was applied during cardiac diastole to simulate aortic counterpulsation. Stimulation was performed during various hemodynamic conditions. RESULTS: A standardised surgical procedure suitable for long term studies was established during six experiments. An APPC, with 70-80 mm filling volume, was found to be of optimal size. In another eight experiments, hemodynamic measurements were performed. Under stable hemodynamic conditions the stimulation of the biological skeletal muscle ventricle induced a significant increase of mean arterial pressure by 14% and mean diastolic pressure by 26%. During pharmacologically induced periods of cardiac failure, the stimulation of the APPC increased mean arterial pressure by 13% and mean diastolic pressure by 19%. In all eight experiments, the diastolic peak pressure reached supra-systolic values during stimulation. CONCLUSIONS: The results demonstrate the hemodynamic efficacy of this newly designed biological skeletal muscle ventricle as an aortic counterpulsation device. Chronic experiments using a preconditioned fatigue-resistant muscle will further help to evaluate its possible clinical significance.

Animals↗

Heparin sensitive and resistant vascular smooth muscle cells: biology and role in restenosis.

Vascular smooth muscle cells (VSMC)s are characterized by their acute growth inhibition by heparin and heparan sulfates; however, recently the isolation of VSMCs which display greatly diminished sensitivity to the antiproliferative action of heparin have been reported. These heparin resistant (HR) VSMCs have been derived through multiple passage of normal rat VSMCs in culture media containing high heparin doses, by transformation of VSMCs with oncogene-containing vectors, or have been isolated from vascular tissues of spontaneously hypertensive rats, healthy humans, or humans with restenosis where their presence is not limited to sites of injury. Initial characterizations of HR VSMCs are reviewed, and here we propose a definition of HR VSMCs. To date the mechanisms underlying heparin insensitivity remain elusive. Further study of HR VSMCs may expand our understanding of cell growth regulation by heparin, establish whether HR VSMCs contribute to the reported failure of heparin to combat restenosis in humans, and identify cellular mechanisms driving certain vascular proliferative diseases.

Animals↗

Effects of intramuscular needle position on motor unit action potential metrics.

It is unclear whether there are clinically significant differences in amplitude, duration, and numbers of turns and phases if an electromyographic (EMG) study is performed near to, or far from, the end-plate zone. The effects of temporal dispersion of arriving muscle-fiber action potentials on quantitative motor unit action potential (MUAP) metrics were assessed in simulated and biologic muscles. Two muscle simulation models were studied with electrode recording positions near the motor end-plate zone and 50-75 mm away. When the electrode was moved away from the end-plate zone, averages of 20 MUAPs significantly decreased in amplitude and area, and increased in numbers of turns and phases, but there was no significant change in duration. In biologic muscles (both normal and pathologic), similar changes in average metrics were observed, but to lesser degrees; few were statistically significant. Zones of innervation in biologic muscles are broadly distributed and, during routine electrode studies, distances between random electrode placements and end-plate zones are therefore relatively short, leading to clinically insignificant changes in quantitative MUAP metrics with distance from the end-plate zone. Thus, electrode position within a muscle is unlikely to affect clinical MUAP interpretation.

Action Potentials↗

Calcium-loaded microsomes from uterine smooth muscle. A biological system to test for calcium ionophore action of prostaglandins.

Smooth muscle microsomal vesicles were loaded with calcium in the presence of oxalate and ATP. The intact vesicles that contained calcium oxalate crystals were separated by ultracentrifugation from empty vesicles. This results in a unique model system, composed of a biologically active membrane with virtually all of the calcium inside. Intravesicular calcium is differentiated from externally bound calcium using ionophore X537A and EGTA. EGTA released calcium slowly with a half time of 93 min. The ionophore X537A rapidly released calcium with a half time of 12 min. This model can be used to test for calcium ionophoretic action. Prostaglandin (PG) E2 and prostacyclin (PGI2) were tested in this system. We found that PGE2 and PGI2 did not change calcium permeability.

Calcium↗