The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis

Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research & Development, Eastern Point Rd., MS8220-3120, Groton, CT 06340, USA.
Proceedings of The Nutrition Society (Impact Factor: 5.27). 06/2004; 63(2):279-86. DOI: 10.1079/PNS2004335
Source: PubMed


Intracellular Ca(2+) plays an important role in skeletal muscle excitation-contraction coupling and also in excitation-transcription coupling. Activity-dependent alterations in muscle gene expression as a result of increased load (i.e. resistance or endurance training) or decreased activity (i.e. immobilization or injury) are tightly linked to the level of muscle excitation. Differential expression of genes in slow- and fast-twitch fibres is also dependent on fibre activation. Both these biological phenomena are, therefore, tightly linked to the amplitude and duration of the Ca(2+) transient, a signal decoded downstream by Ca(2+)-dependent transcriptional pathways. Evidence is mounting that the calcineurin-nuclear factor of activated T-cells pathway and the Ca(2+)/calmodulin-dependent kinases (CaMK) II and IV play important roles in regulating oxidative enzyme expression, mitochondrial biogenesis and expression of fibre-type specific myofibrillar proteins. CaMKII is known to decode frequency-dependent information and is activated during hypertrophic growth and endurance adaptations. Thus, it was hypothesized that CaMKII, and possibly CaMKIV, are down regulated during muscle atrophy and levels of expression of CaMKII alpha, -II beta, -II gamma and -IV were assessed in skeletal muscles from young, aged and denervated rats. The results indicate that CaMKII gamma, but not CaMKIIalpha or -beta, is up regulated in aged and denervated soleus muscle and that CaMKIV is absent in skeletal but not cardiac muscle. Whether CaMKII gamma up-regulation is part of the pathology of wasting or a result of some adaptational response to atrophy is not known. Future studies will be important in determining whether insights from the adaptational response of muscle to increased loads will provide pharmacological approaches for increasing muscle strength or endurance to counter muscle wasting.

Download full-text


Available from: Eva R Chin, May 26, 2015
  • Source
    • "Myoblast differentiation is a multistep process that crucially depends on the generation of Ca 2+ signals, which in turn allow the activation of transcription factors and of a great variety of Ca 2+ -dependent kinases or phosphatases [1] [2]. For instance, the muscle specific transcription factors myogenin and MEF2 (myocyte enhance factor 2) [3] [4] that are expressed early during the differentiation, required the activation of calmodulin kinase (CaMK) and calcineurin [5] [6] [7] [8], two Ca 2+ -dependent enzymes. In myoblasts, intracellular Ca 2+ elevations result from endoplasmic reticulum (ER) Ca 2+ release and/or from plasma membrane Ca 2+ entry [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytosolic Ca2+ signals are fundamental for the early and late steps of myoblast differentiation and are, as in many cells, generated by Ca2+ release from internal stores as well as by plasma membrane Ca2+ entry. Our recent studies identified the store-operated Ca2+ channels, Orai1 and TRPC1&C4, as crucial for the early steps of human myogenesis and for the late fusion events. In the present work, we assessed the role of the inositol-1,4,5 tris-phosphate receptor (IP3R) type 1 during human myoblast differentiation. We demonstrated, using siRNA strategy that IP3R1 is required for the expression of muscle-specific transcription factors such as myogenin and MEF2 (myocyte enhancer factor 2), and for the formation of myotubes. The knockdown of IP3R1 strongly reduced endogenous spontaneous Ca2+ transients, and attenuated store-operated Ca2+ entry. As well, two Ca2+-dependent key enzymes of muscle differentiation, NFAT and CamKII are down-regulated upon siIP3R1 treatment. On the contrary, the overexpression of IP3R1 accelerated myoblasts differentiation. These findings identify Ca2+ release mediated by IP3R1 as an essential mechanism during the early steps of myoblast differentiation.
    Cell Calcium 11/2014; 56(6). DOI:10.1016/j.ceca.2014.10.014 · 3.51 Impact Factor
  • Source
    • "For example, the differentiation of slowtwitch myofibers requires a particular time-course of Ca 2+ changes to activate Ca 2+ -calmodulin-dependent kinases CaMKII and CaMKIV, which lead to mitochondrial biogenesis and induction of oxidative enzymes. These effects are mediated by mechanisms involving the CREB-mediated expression of PGC-1α, one of the most important coactivators of PPAR-γ and inducers of mitochondrial biogenesis (Chin, 2004). Preliminary observations indicate that 24 h treatment of OPs with the PPAR-γ agonists 15d- PGJ 2 or pioglitazone increases the expression of PGC-1α (Bernardo et al., unpublished observation), which could ultimately lead to the biogenesis of mitochondria, and in turn, to the observed increase of complex IV activity and recovery from rotenone effects (Figure 3). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Peroxisome proliferator-activated receptor-γ (PPAR-γ) is one of the most studied nuclear receptor since its identification as a target to treat metabolic and neurological diseases. Besides exerting anti-inflammatory and neuroprotective effects, PPAR-γ agonists, such as the insulin-sensitizing drug pioglitazone, promote the differentiation of oligodendrocytes (OLs), the myelin-forming cells of the CNS. In addition, PPAR-γ agonists increase OL mitochondrial respiratory chain activity and OL ability to respond to environmental signals with oscillatory Ca2+ waves. Both OL maturation and oscillatory Ca2+ waves are prevented by the mitochondrial inhibitor rotenone and restored by PPAR-γ agonists, suggesting that PPAR-γ promotes myelination through mechanisms involving mitochondria.
    Biological Chemistry 06/2013; 394(12). DOI:10.1515/hsz-2013-0152 · 3.27 Impact Factor
  • Source
    • "It will be important to determine whether RyR1 modification can be altered by changes in physical activity between single bouts of exercise. Besides affecting myofiber contractility, pRyR1Ser2843-mediated changes in sarcoplasmatic Ca2+levels may also offer an important function in exercise-induced Ca2+signaling, as elevated sarcoplasmic Ca2+levels may trigger enhanced Ca2+binding to its targets, including NFAT, Calcineurin and CaMKIV [34]. These factors influence the modulation of myofiber plasticity, e.g. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: While ryanodine receptor 1 (RyR1) critically contributes to skeletal muscle contraction abilities by mediating Ca(2+)ion oscillation between sarcoplasmatic and myofibrillar compartments, AMP-activated protein kinase (AMPK) senses contraction-induced energetic stress by phosphorylation at Thr(172). Phosphorylation of RyR1 at serine(2843) (pRyR1Ser(2843)) results in leaky RyR1 channels and impaired Ca(2+)homeostasis. Because acute resistance exercise exerts decreased contraction performance in skeletal muscle, preceded by high rates of Ca(2+)-oscillation and energetic stress, intense myofiber contractions may induce increased RyR1 and AMPK phosphorylation. However, no data are available regarding the time-course and magnitude of early RyR1 and AMPK phosphorylation in human myofibers in response to acute resistance exercise. PURPOSE: Determine the effects and early time-course of resistance exercise on pRyR1Ser(2843) and pAMPKThr(172) in type I and II myofibers. METHODS: 7 male subjects (age 23±2 years, height: 185±7 cm, weight: 82±5 kg) performed 3 sets of 8 repetitions of maximum eccentric knee extensions. Muscle biopsies were taken at rest, 15, 30 and 60 min post exercise. pRyR1Ser(2843) and pAMPKThr(172) levels were determined by western blot and semi-quantitative immunohistochemistry techniques. RESULTS: While total RyR1 and total AMPK levels remained unchanged, RyR1 was significantly more abundant in type II than type I myofibers. pRyR1Ser(2843) increased 15 min and peaked 30 min (p<0.01) post exercise in both myofiber types. Type I fibers showed relatively higher increases in pRyR1Ser(2843) levels than type II myofibers and remained elevated up to 60 min post resistance exercise (p<0.05). pAMPKThr(172) also increased 15 to 30 min post exercise (p<0.01) in type I and II myofibers and in whole skeletal muscle. CONCLUSION: Resistance exercise induces acutely increased pRyR1Ser(2843) and concomitantly pAMPKThr(172) levels for up to 30 min in resistance exercised myofibers. This provides a time-course by which pRyR1Ser(2843) can mechanistically impact Ca(2+)handling properties and consequently induce reduced myofiber contractility beyond immediate fatiguing mechanisms.
    PLoS ONE 11/2012; 7(11):e49326. DOI:10.1371/journal.pone.0049326 · 3.23 Impact Factor
Show more

Similar Publications