From Lyles board:
My science knowledge is weak (but thanks to you guys, improving
), but is this correct? I thought these so called pump-related factors had more of an effect on erk1/2.
Comments, thoughts?
Maybe I put too much emphasis on tension and not enough on "fatigue"
Nathan
and Elzi's comments:[b said:Quote[/b] ]http://www.ncbi.nlm.nih.gov/entrez/...t_uids=15574487
Long story short......calcium accumulation, rather then force or tension, are responsible for increased p38 MAPK stimulation, which is involved in hypertrophy signaling. Isometric contractions capable of activating p38 MAPK had no effect on ERK1/2, but concentric contractions with or without force, and an increase in reactive oxygen species, do.
Inhibition of cross-bridge formation has no effect on contraction-associated phosphorylation of p38 MAPK in mouse skeletal muscle.
Dentel JN, Blanchard SG, Ankrapp DP, McCabe LR, Wiseman RW.
Molecular Imaging Research Center, Dept. of Physiology, Michigan State Univ., 2201 Biomedical and Physical Sciences Bldg., East Lansing, MI 48824, USA.
Mitogen-activated protein kinases (MAPKs), in particular p38 MAPK, are phosphorylated in response to contractile activity, yet the mechanism for this is not understood. We tested the hypothesis that the force of contraction is responsible for p38 MAPK phosphorylation in skeletal muscle. Extensor digitorum longus (EDL) muscles isolated from adult male Swiss Webster mice were stimulated at fixed length at 10 Hz for 15 min and then subjected to Western blot analysis for the phosphorylation of p38 MAPK and ERK1/2. Contralateral muscles were fixed at resting length and were not stimulated. Stimulated muscles showed a 2.5-fold increase in phosphorylated p38 MAPK relative to nonstimulated contralateral controls, and there was no change in the phosphorylation of ERK1/2. When contractile activity was inhibited with N-benzyl-p-toluene sulfonamide (BTS), a specific inhibitor of actomyosin ATPase, force production decreased in both a time- and concentration-dependent manner. Preincubation with 25, 75, and 150 microM BTS caused 78+/-4%, 97+/-0.2%, and 99+/-0.2% inhibition in contractile force, respectively, and was stable after 30 min of treatment. Fluorescence measurements demonstrated that Ca2+ cycling was minimally affected by BTS treatment. Surprisingly, BTS did not suppress the level of p38 MAPK phosphorylation in stimulated muscles. These data do not support the view that force generation per se activates p38 MAPK and suggest that other events associated with contraction must be responsible.
[b said:Quote[/b] ]Careful. This was an ex vivo study with a mouse model, using extensor digitorum longus (EDL) muscles and a force transducer, delivering isometric contractions by electrical stimulation. The molecular pathways may not be the same as those associated with other contractions (so a recent molecular biology study demonstrates). And certainly has limited extrapolation regarding voluntary contractions in an intact organism.
Also, keep in mind that hypertrophy is multifactorial with some pathways overlapping or compensating.
Excerpted from the paper:
"MAPK phosphorylation and mechanical signaling. Mechanical stress is a change in force per cross-sectional area, whereas mechanical strain is a change in force per change in length. Muscles contract in vivo, with small changes in muscle length (low component of mechanical strain) depending on pennation, but force per cross-sectional area increases substantially during contraction (high component of mechanical stress) (12, 18, 20). Hence, in the isometric contraction model used in the present study, mechanical stress was the dominant physical force. In contrast, contractions with concurrent increases in length (eccentric contractions) have a larger strain component than isometric contractions do and can cause substantial damage to the sarcolemmal membrane and the SR (14, 21). Thus, for studies of mechanical signaling, increases in the proportion of mechanical strain to overall muscle loading may result in substantial muscle damage (2, 25). On the basis of these facts, interpretation of the intracellular signaling by MAPKs in exercising muscle may be confounded by underlying membrane and organelle damage. By using isometric contractions, we designed the present study to minimize mechanical strain (or any damage) under physiological conditions.
The results of the present study show two important findings with respect to mechanical stress in isometric contractions. First, Fig. 4 shows that p38 MAPK responded to contractile activity because there was robust phosphorylation in stimulated muscles relative to the contralateral resting controls. However, the inhibition of force production through a loss in cross-bridge formation from BTS administration (Fig. 3) did not attenuate the phosphorylation response (Fig. 4). This supports the argument that p38 MAPK, while activated as a consequence of electrical stimulation, does not respond to mechanical loading and that some other aspect of physiological activity associated with contraction, perhaps metabolic in nature, must be responsible. This result conflicts with a previous study of isolated superfused rat EDL muscles in which the investigators concluded that ERK1/2 was sensitive to a metabolic signal, whereas p38 MAPK was sensitive to mechanical force (40). The disagreement of those previous results with those of the present study might be explained by the nature of the contractions performed. Wretman et al. (40) used tetanic contractions with changes in muscle length, eccentric and concentric, resulting in a strain component not present in the experiments described in the present study. Strain-dependent activation of p38 MAPK has been shown in rat EDL muscle. Boppart et al. (5) showed that passive stretch of rat EDL with forces as small as 0.06 N resulted in a fivefold increase in p38 MAPK phosphorylation. Their study also showed similar trends in slow-twitch soleus muscles; however, the relative increases in p38 MAPK phosphorylation were not as dramatic until mechanical strain was >0.24 N, suggesting fiber-specific effects. However, ERK1/2 phosphorylation with passive stretch was identical independent of muscle fiber-type content. Taken together, these results suggest that ERK1/2 responds to strain in the presence or absence of active force generation and is not fiber type dependent, while p38 MAPK responds to events associated with muscle activation but is not dependent on force production. Consistent with this conclusion is that isometric contractions did not activate ERK1/2 in the present study (Fig. 6).....
Concluding remarks. On the basis of the results of the present study, we conclude that p38 MAPK is significantly activated in isolated mouse fast-twitch muscle in response to chronic isometric contractions. The observation that the fold increases in p38 MAPK phosphorylation were similar in stimulated muscle in the absence and presence of BTS indicates that mechanical stress is not the signaling mechanism for activation of p38 MAPK. Furthermore, the observation that ERK1/2 was not phosphorylated in response to chronic isometric contractions suggests that ERK1/2 responds to strain in the presence or absence of active force generation, while p38 MAPK responds to events associated with muscle activation but not force production. These putative signaling mechanisms could include changes in intracellular Ca2+ and/or changes in ATP-free energy homeostasis. "
My science knowledge is weak (but thanks to you guys, improving
), but is this correct? I thought these so called pump-related factors had more of an effect on erk1/2.Comments, thoughts?
Maybe I put too much emphasis on tension
and not enough on "fatigue"
Nathan