Harmonizing Magnetic Mitohormetic Regenerative Strategies: Developmental Implications of a Calcium-Mitochondrial Axis Invoked by Magnetic Field Exposure

Abstract

Mitohormesis is a process whereby mitochondrial stress responses, mediated by reactive oxygen species (ROS), act cumulatively to either instill survival adaptations (low ROS levels) or to produce cell damage (high ROS levels). The mitohormetic nature of extremely low-frequency electromagnetic field (ELF-EMF) exposure thus makes it susceptible to extraneous influences that also impinge on mitochondrial ROS production and contribute to the collective response. Consequently, magnetic stimulation paradigms are prone to experimental variability depending on diverse circumstances. The failure, or inability, to control for these factors has contributed to the existing discrepancies between published reports and in the interpretations made from the results generated therein. Confounding environmental factors include ambient magnetic fields, temperature, the mechanical environment, and the conventional use of aminoglycoside antibiotics. Biological factors include cell type and seeding density as well as the developmental, inflammatory, or senescence statuses of cells that depend on the prior handling of the experimental sample. Technological aspects include magnetic field directionality, uniformity, amplitude, and duration of exposure. All these factors will exhibit manifestations at the level of ROS production that will culminate as a unified cellular response in conjunction with magnetic exposure. Fortunately, many of these factors are under the control of the experimenter. This review will focus on delineating areas requiring technical and biological harmonization to assist in the designing of therapeutic strategies with more clearly defined and better predicted outcomes and to improve the mechanistic interpretation of the generated data, rather than on precise applications. This review will also explore the underlying mechanistic similarities between magnetic field exposure and other forms of biophysical stimuli, such as mechanical stimuli, that mutually induce elevations in intracellular calcium and ROS as a prerequisite for biological outcome. These forms of biophysical stimuli commonly invoke the activity of transient receptor potential cation channel classes, such as TRPC1.

Keywords: bioelectromagnetics; bioengineering; magnetic field therapy; magnetoreception; regenerative medicine; tissue engineering.

Figure 1

Most common frequencies and amplitudes of magnetic fields used in magnetoreceptive paradigms. (A) Magnetic field frequencies commonly employed in studies examining the biological effect of Static/Standing Magnetic Field (SMF), Geomagnetic Field (GMF), Extremely Low-Frequency Electromagnetic Fields (ELF-EMFs), and Radical Pair Mechanism (RPM), including photons of light. ELF-EMFs are also commonly referred to as Pulsed Electromagnetic Fields (PEMFs). Frequencies are shown against the backdrop of the entire electromagnetic spectrum. IR and UV are infrared and ultraviolet level radiations, respectively. Colors are the visible light range. (B) Range of magnetic field strengths commonly employed in studies examining the biological effect of SMF, GMF (~25–65 µT depending on location on the planet), ELF-EMFs, and RPM. This figure provides the most common values for magnetic field frequencies and amplitudes for the given applications; deviations from these values have been reported. Magnetic field strengths are given in Tesla (T) or Gauss (G). In this review, we employ Tesla for consistency with most published studies. 1 Tesla = 10⁴ Gauss. Panel B adapted from [4]. (Created with BioRender.com).

Figure 2

Distinct magnetic field symmetries and waveforms commonly employed in bioelectromagnetic studies. (Ai) Temporal characteristics of distinct PEMF signals where a = positive amplitude; b = positive width; c = negative amplitude; d = negative width. Shown is the electrical output from the signal generator, which, in ideal cases, approximates the magnetic field temporal characteristics, but is not always the case as it depends on accurate coil-electronic matching. (Aii) Repetition frequency of a barrage of pulses. The signal becomes more continuous as e approaches d. In this example, the magnetic pulses are asymmetrical, starting and returning to zero magnetic field, without ever crossing zero magnetic field. (Aii) Example of a symmetrical waveform. Both (Aii) and (Aiii) have the same absolute magnitude (peak-to-trough), but (Aiii) has half the relative amplitude above and below 0 mT. Symmetrical signals also generate magnetic fields that change directions after crossing 0 mT, which would have developmental implications (see Section 10). (B) Distinct waveforms as indicated. A rapid rise time (Tesla/second) to the magnetic signal is a determinant feature for biological response [59] that will ultimately translate to the efficacy of a particular waveform. The different waveforms are derived from variations in this steepness factor. (Panel Ai) adapted from [68]. (Created with BioRender.com).

Figure 3

Hypothetical model of magnetoreception and the factors that may influence its operation. Orange circles represent Ca²⁺ ions and red circles represent ROS. Whether all aspects of the depicted enzymatic and transcriptional response cascade are recruited by all forms of magnetic stimulation, and in what tissues, remains to be scientifically determined. Environmental factors such as photons, temperature, and pH, as they influence enzymatic and mitochondrial efficiencies, as well as are detected by TRP channels, will influence magnetic mitohormetic responses. The transcriptional repercussions of magnetically stimulated Ca²⁺ and ROS increments over mitochondrial function were previously reviewed elsewhere [38]. (Created with BioRender.com).

Figure 4

Differences in magnetic field uniformity obtained between a Helmholtz coil and a bar magnet. (A) Magnetic field lines generated with a Helmholtz coil. In this instance, clockwise electrical current flow through the coil produces an upwardly directed magnetic field. (B) Magnetic field lines associated with a bar magnet. Red and blue are north and south poles, respectively. (C) Field uniformity within a Helmholtz coil configuration. (D) Field uniformity associated with a bar magnet. A sample (conical tube) within the uniform region of a Helmholtz coil will receive uniform magnetic field exposure, whereas a sample at a distance from a point source of magnetic fields, such as a bar magnet, will experience non-uniform field exposure. (Created with BioRender.com).