Mechanotransduction is a process where cells sense their surroundings and convert the physical forces in their environment into an appropriate response. Calcium plays a crucial role in the translation of such forces to biochemical signals that control various biological processes fundamental in muscle development. The mechanical stimulation of muscle cells may for example result from stretch, electric and magnetic stimulation, shear stress, and altered gravity exposure. The response, mainly involving changes in intracellular calcium concentration then leads to a cascade of events by the activation of downstream signaling pathways. The key calcium-dependent pathways described here include the nuclear factor of activated T cells (NFAT) and mitogen-activated protein kinase (MAPK) activation. The subsequent effects in cellular homeostasis consist of cytoskeletal remodeling, cell cycle progression, growth, differentiation, and apoptosis, all necessary for healthy muscle development, repair, and regeneration. A deregulation from the normal process due to disuse, trauma, or disease can result in a clinical condition such as muscle atrophy, which entails a significant loss of muscle mass. In order to develop therapies against such diseased states, we need to better understand the relevance of calcium signaling and the downstream responses to mechanical forces in skeletal muscle. The purpose of this review is to discuss in detail how diverse mechanical stimuli cause changes in calcium homeostasis by affecting membrane channels and the intracellular stores, which in turn regulate multiple pathways that impart these effects and control the fate of muscle tissue.

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Calcium's Role in Mechanotransduction during Muscle Development

Life on earth has evolved in a sea of natural electromagnetic (EM) fields. Over the past century, this natural environment has sharply changed with introduction of a vast and growing spectrum of man-made EM fields. From models based on equilibrium thermodynamics and thermal effects, these fields were initially considered too weak to interact with biomolecular systems, and thus incapable of influencing physiological functions. Laboratory studies have tested a spectrum of EM fields for bioeffects at cell and molecular levels, focusing on exposures at athermal levels. A clear emergent conclusion is that many observed interactions are not based on tissue heating. Modulation of cell surface chemical events by weak EM fields indicates a major amplification of initial weak triggers associated with binding of hormones, antibodies, and neurotransmitters to their specific binding sites. Calcium ions play a key role in this amplification. These studies support new concepts of communication between cells across the barriers of cell membranes; and point with increasing certainty to an essential physical organization in living matter, at a far finer level than the structural and functional image defined in the chemistry of molecules. New collaborations between physical and biological scientists define common goals, seeking solutions to the physical nature of matter through a strong focus on biological matter. The evidence indicates mediation by highly nonlinear, nonequilibrium processes at critical steps in signal coupling across cell membranes. There is increasing evidence that these events relate to quantum states and resonant responses in biomolecular systems, and not to equilibrium thermodynamics associated with thermal energy exchanges and tissue heating.

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Biological effects of electromagnetic fields

An international seminar was held June 4-6, 1997, on the biological effects and related health hazards of ambient or environmental static and extremely low frequency (ELF) electric and magnetic fields (0-300 Hz). It was cosponsored by the World Health Organization (WHO), the International Commission on Non-Ionizing Radiation Protection (ICNIRP), the German, Japanese, and Swiss governments. Speakers provided overviews of the scientific literature that were discussed by participants of the meeting. Subsequently, expert working groups formulated this report, which evaluates possible health effects from exposure to static and ELF electric and magnetic fields and identifies gaps in knowledge requiring more research to improve health risk assessments. The working groups concluded that, although health hazards exist from exposure to ELF fields at high field strengths, the literature does not establish that health hazards are associated with exposure to low-level fields, including environmental levels. Similarly, exposure to static electric fields at levels currently found in the living and working environment or acute exposure to static magnetic fields at flux densities below 2 T, were not found to have demonstrated adverse health consequences. However, reports of biological effects from low-level ELF-field exposure and chronic exposure to static magnetic fields were identified that need replication and further study for WHO to assess any possible health consequences. Ambient static electric fields have not been reported to cause any direct adverse health effects, and so no further research in this area was deemed necessary.

Interaction of static and extremely low frequency electric and magnetic fields with living systems: health effects and research needs.

Diverse animals can detect magnetic fields but little is known about how they do so. Three main hypotheses of magnetic field perception have been proposed. Electrosensitive marine fish might detect the Earth's field through electromagnetic induction, but direct evidence that induction underlies magnetoreception in such fish has not been obtained. Studies in other animals have provided evidence that is consistent with two other mechanisms: biogenic magnetite and chemical reactions that are modulated by weak magnetic fields. Despite recent advances, however, magnetoreceptors have not been identified with certainty in any animal, and the mode of transduction for the magnetic sense remains unknown.

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The physics and neurobiology of magnetoreception

Electrification in developed countries has progressively increased the mean level of extremely low-frequency electromagnetic fields (ELF-EMFs) to which populations are exposed; these humanmade fields are substantially above the naturally occurring ambient electric and magnetic fields of approximately 10(-4) Vm(-1) and approximately 10(-13) T, respectively. Several epidemiological studies have concluded that ELF-EMFs may be linked to an increased risk of cancer, particularly childhood leukemia. These observations have been reinforced by cellular studies reporting EMF-induced effects on biological systems, most notably on the activity of components of the pathways that regulate cell proliferation. However, the limited number of attempts to directly replicate these experimental findings have been almost uniformly unsuccessful, and no EMF-induced biological response has yet been replicated in independent laboratories. Many of the most well-defined effects have come from gene expression studies; several attempts have been made recently to repeat these key findings. This review analyses these studies and summarizes other reports of major cellular responses to EMFs and the published attempts at replication. The opening sections discuss quantitative aspects of exposure to EMFs and the incidence of cancers that have been correlated with such fields. The concluding section considers the problems that confront research in this area and suggests feasible strategies.

Biological responses to electromagnetic fields

A physical mechanism is suggested for a resonant interaction of weak magnetic fields with biological systems. An ion inside a Ca(2+)-binding protein is approximated by a charged oscillator. A shift in the probability of ion transition between different vibrational energy levels occurs when a combination of static and alternating magnetic fields is applied. This in turn affects the interaction of the ion with the surrounding ligands. The effect reaches its maximum when the frequency of the alternating field is equal to the cyclotron frequency of this ion or to some of its harmonics or sub-harmonics. A resonant response of the biosystem to the magnetic field results. The proposed theory permits a quantitative explanation for the main characteristics of experimentally observed effects.

Possible mechanism for the influence of weak magnetic fields on biological systems.

The effects of super high frequency (SHF) microwaves (34-78 GHz) on rates of spontaneous firing of the slowly adapting, stretch-receptor neurons of crayfish were studied. Initially, irradiation of continuously perfused, fluid-cooled preparations at power densities to 250 mW/cm2 caused a transient decrease in the rate of spontaneous firing (the dynamic response). Subsequently, with extinction of the SHF field, the rate of firing increased, finally stabilizing at pre-exposure levels (stationary phase). Rates of firing also increased when the receptor muscle was stretched, and they were inversely correlated with small, field-induced increases of temperature (approximately 1.5 degrees C). The response to SHF radiation did not depend on frequency if temperature of the medium was constant. No resonant peaks were found when the millimeter range of frequencies was scanned.

Millimeter-wave effects on electric activity of crayfish stretch receptors.

Comments on “clarification and application of ion parametric resonance model for magnetic field interactions with biological systems” by Blanchard and Blackman

V. V. Lednev

Papers

Possible mechanism for the influence of weak magnetic fields on biological systems.

Millimeter-wave effects on electric activity of crayfish stretch receptors.

Comments on “clarification and application of ion parametric resonance model for magnetic field interactions with biological systems” by Blanchard and Blackman