Exercise and health: can biotechnology confer similar benefits?

Abstract

Education and public policies are largely failing to encourage people to exercise. Could our knowledge of exercise biology lead to pharmaceutical treaments that could confer the same benefits as exercise?

Figure 1. Specialized Myofibers in a Mammalian Skeletal Muscle

A cross-section of the gastrocnemius muscle of a mouse has been stained to detect myoglobin, which is found selectively in slow oxidative and fast oxidative myofibers (stained brown), but not in fast glycolytic myofibers (unstained). Human muscles exhibit a similar mosaic pattern. In response to sustained periods of motor nerve stimulation repeated daily for several weeks, the percentage of myofibers that contain myoglobin is increased, in synchrony with an increased abundance of mitochondria and a shift of myosin subtypes from fast glycolytic to slow or fast oxidative.

Figure 2. Molecular Signaling Pathways Link Changes in Contractile Activity to Changes in Gene Expression That Establish Myofiber Diversity

A tonic pattern of motor nerve activity promotes changes in intracellular calcium that trigger a variety of intracellular events that modify the function of nuclear transcription factors. The pathway transduced by calcineurin and NFAT is highlighted in larger type. Other signals are received by cell surface receptors to activate similar or parallel signaling events. Signaling proteins that participate in transducing effects of contractile activity to specific genes include ion channels (TRP), scaffolding proteins (Homer), protein phosphatases and protein kinases (calcineurin, CAMK, p38MAPK), DNA-binding transcription factors (shown in red; NFAT, MEF2, PGC-1, ATF2), and endogenous inhibitors (shown in blue; GSK3, HDAC, and MCIP) (inhibitors antagonize gene activation via the pathways indicated, in some cases acting as negative feedback regulators).

Figure 3. Proposed Model for Cellular Memory, Based on Activity-Induced Changes in TRPC3—A Putative Store-Operated Calcium Channel

Neural activation triggers muscle contraction by releasing calcium stored within the sarcoplasmic reticulum (SR) through mechanisms that involve channel proteins called dihydropyridine receptors (DHPR) and ryanodine receptors (RYR). Inactive myofibers have a low abundance of TRPC3 channels, and calcium released from SR is not sufficient to maintain the calcium-regulated transcription factor NFAT in the nucleus. Under conditions of tonic activity (training stimulus), TRPC3 channels become more abundant, and are regulated by the scaffold protein Homer, which binds RYR. Under these conditions, the combined effect of calcium entering the cell via TRPC3 channels and exiting the SR via RYR channels maintains NFAT in the nucleus, where it promotes transcription of genes that establish the slow oxidative phenotype in myofibers. Once the slow oxidative phenotype is established (trained myofiber), the continued expression of TRPC3 allows this state to be maintained even with a less intensive tonic activity pattern of neural stimulation. (Figure adapted from [40].)