Myoglobin

Myoglobin (Mb) is an oxygen-binding hemoprotein (17.1 kDa) in myocytes in skeletal muscle and myocardial muscle. The total amount of myoglobin in an adult male is about 120-150 g (Åkeson et al., 1968). Five different isoforms of myoglobin have been identified in humans, but ∼95% of Mb consists of two isoforms, Mb-I and Mb-II, which differ by only one residue (Chintapalli et al., 2018). About 10% of the iron in the body is bound to myoglobin. Mb has a higher affinity for oxygen than red blood cell haemoglobin; as a monomer it has only one haem, while the tetrameric haemoglobin has four haem groups. Myoglobin has a hyperbolic oxygen-binding curve, while haemoglobin, due to the co-operativity of oxygen binding, has sigmoidal oxygen-binding curve. During exercise, deoxymyoglobin can be observed only after haemoglobin is >70% deoxygenated (Mancini et al., 1994). The early studies of the oxygen-binding relationship to the oxygen tension had to be conducted in low temperatures to avoid the rapid auto-oxidation of myoglobin(II) to metmyoglobin(III), but the later spectroscopy studies have confirmed that the myoglobin dissociation curve can be well fitted by the Hill equation

, where SMbO2 is the saturation of myoglobin, pO2 is the partial pressure of oxygen (oxygen tension), and P50 is the pO2 at which myoglobin is half-saturated with oxygen. pO2 is highly dependent on temperature, and slightly correlated to pH (Schenkman et al., 1997). Hyperbolic dissociation curve buffers the intracellular pO2: when Mb is near its P50, a fall in Mb oxygen saturation results in proportionally smaller decrease in pO2 (Gayeski et al., 1985).

Myoglobin is excluded from the mitochondrial and nuclear volumes and the volume occupied by the contractile elements. Therefore the concentration of myoglobin is several-fold higher in the cell volume crucial to oxygen transport than in the total cell volume. Mitochondrial outer membrane separates sarcoplasmic myoglobin from cytochrome c oxidase and the proteins of electron transport and oxidative phosphorylation, which are located in the inner mitochondrial membrane. Myoglobin binds nonspecifically to the phospholipids of the mitochondrial outer membrane, which promotes conformational changes near the Mb heme pocket, and decreases the affinity of Mb for O2 (Postnikova & Shekhovtsova, 2018). Lipid bilayers are highly permeable to O2, and oxygen concentration is high and diffusion is fast in the interleaflet region of the membrane (Riistama et al., 1996; Ghysels et al., 2017).

Oxymyoglobin molecules, each carrying one O2 molecule, buffers the oxygen concentration, and facilitates the flux of oxygen from RBC to mitochondria (Gayeski et al., 1985; Covell & Jacquez, 1987; Postnikova & Shekhovtsova, 2018). The diffusion rate of myoglobin itself is not be significant in the transport of oxygen, since it is only about 1/20 of that of free O2, but the concentration of myoglobin is 30-100 -fold higher than the concentration of free O2 in working muscle. There are no large intracellular concentration gradients for oxygen or other metabolites, not only because of passive diffusion, but due to the active intracellular circulation (Hochachka, 1999). Even when subcellular spectrometry of Mb shows intracellular gradients of [O2], mitochondria can still sustain electron transfer (Takahashi & Asano, 2002). The rate of MbO2 deoxygenation is determined by the respiratory activity of the mitochondria (Postnikova & Shekhovtsova, 2018).

Myoglobin content in the femoral muscle of sedentary normal subjects is ∼4-6 mg/g (Möller & Sylvén, 1981; Svedenhag et al., 1983; Jansson et al., 1988; Mancini et al., 1994). Physical training increases the activity of oxidative enzymes but does not increase muscle Mb content (Svedenhag et al., 1983; Sylvén et al., 1984; Masuda et al., 1999), but leg muscle immobilization increases it while decreasing oxidative enzyme activities (Jansson et al., 1988). Owing to the storage capacity of myoglobin, ∼4 min ischemia is needed to deplete the oxygen stores in resting skeletal muscle, as measured in human forearm based on creatine phosphate (PCr) kinetics (Blei et al., 1993). In rat heart, Mb can prolong heart function for a few seconds (Chung & Jue, 1996). In humans, myocardial Mb concentration is about half of that in skeletal muscle (Sylvén et al., 1984). In skeletal muscle, the ratio of [Hb] to [Mb] is >5 (Grassi et al., 1999).

In pig hearts, Mb content is 0.36 mmol/kg (6.1±0.6 g/kg wet weight) (Arai et al., 1999). Heme concentration (due to Hb) is 0.2 mmol/kg (Nighswander-Rempel et al., 2002). Under normal conditions, Hb in venous blood from porcine myocardial tissue is ∼70% saturated, and also Mb mostly saturated (Nighswander-Rempel et al., 2002).

Myoglobin knockout mice (Myo-/-) are viable, fertile, and without any obvious functional limitations, but as compensatory mechanisms to prevent hypoxia the capillary density and haemoglobin content are increased, and myocardial muscle prefers glucose to palmitate as the fuel (Gödecke et al., 1999; Flögel et al., 2005). Myoglobin content varies greatly among species and muscle groups (Meng et al., 1993).

Carbon monoxide

Carbon monoxide (CO) binds about 250-fold more tightly than O2 to myoglobin and haemoglobin, with higher affinity to Hb than to Mb (Glabe et al., 1998). Inhibition of Mb with CO does not seem to change the respiration rate (Chung et al., 2006).

NO

Myoglobin is involved in both NO oxidation (to nitrite) and nitrite reduction to NO. Intracellular pO2 determines whether Mb is consuming or producing NO, and normal pO2 is close to the P50 of myoglobin.

Fatty acids

Oxygenated form of myoglobin (Oxy-Mb) binds fatty acids by hydrophobic interactions in the core of the protein. Although the binding affinity is relatively low, it can affect lipid and oxygen metabolism due to the high amount of Mb in type 1 myocytes and cardiomyocytes (Chintapalli et al., 2018).


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References:

Gayeski TEJ, Connett RJ, Honig CR. Oxygen transport in rest-work transition illustrates new functions for myoglobin. Am J Physiol. 1985; 248: H914-H921. 10.1152/ajpheart.1985.248.6.H914.

Millikan GA. Muscle haemoglobin. Physiol Rev. 1939; 19: 503-523. doi: 10.1152/physrev.1939.19.4.503.

Möller P, Sylvén C. Myoglobin in human skeletal muscle. Scand J Clin Lab Invest. 1981; 41(5): 479-482. doi: 10.3109/00365518109090486.

Åkeson Å, Björck G, Simon R. On the content of myoglobin in human muscles. Acta Med Scand. 1968; 183: 307-316. doi: 10.1111/j.0954-6820.1968.tb10482.x.

Gros G, Wittenberg BA, Jue T. Myoglobin’s old and new clothes: from molecular structure to function in living cells. J Exp Biol. 2010; 213(Pt 16): 2713-2725. doi: 10.1242/jeb.043075.

Wick M, Pinggera W, Lehmann P: Clinical Aspects and Laboratory - Iron Metabolism, Anemias. 6th edition. Springer, 2011.

Wittenberg BA, Wittenberg JB. Myoglobin-mediated oxygen delivery to mitochondria of isolated cardiac myocytes. Proc Natl Acad Sci USA 1987; 84: 7503-7507.

Wittenberg BA, Wittenberg JB. Transport of oxygen in muscle. Annu Rev Physiol. 1989; 51: 857-878.

Wittenberg JB, Wittenberg BA. Myoglobin function reassessed. J Exp Biol. 2003; 206: 2011-2020.

Wittenberg JB. On optima: the case of myoglobin-facilitated oxygen diffusion. Gene 2007; 398: 156-161.



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Created at: 2017-03-30
Updated at: 2018-12-09
Written by: Vesa Oikonen