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. 2014 Oct 15;592(20):4555-73.
doi: 10.1113/jphysiol.2014.279034. Epub 2014 Jul 18.

Muscle disuse alters skeletal muscle contractile function at the molecular and cellular levels in older adult humans in a sex-specific manner

Damien M Callahan  1 , Mark S Miller  2 , Andrew P Sweeny  1 , Timothy W Tourville  3 , James R Slauterbeck  3 , Patrick D Savage  1 , David W Maugan  2 , Philip A Ades  1 , Bruce D Beynnon  3 , Michael J Toth  4
Affiliations

Muscle disuse alters skeletal muscle contractile function at the molecular and cellular levels in older adult humans in a sex-specific manner

Damien M Callahan et al. J Physiol. .

Abstract

Physical inactivity that accompanies ageing and disease may hasten disability by reducing skeletal muscle contractility. To characterize skeletal muscle functional adaptations to muscle disuse, we compared contractile performance at the molecular, cellular and whole‐muscle levels in healthy active older men and women (n = 15) and inactive older men and women with advanced‐stage, symptomatic knee osteoarthritis (OA) (n = 16). OA patients showed reduced (P < 0.01) knee extensor function. At the cellular level, single muscle fibre force production was reduced in OA patients in myosin heavy chain (MHC) I and IIA fibres (both P < 0.05) and differences in IIA fibres persisted after adjustments for fibre cross‐sectional area (P < 0.05). Although no group differences in contractile velocity or power output were found for any fibre type, sex was found to modify the effect of OA, with a reduction in MHC IIA power output and a trend towards reduced shortening velocity in women, but increases in both variables in men (P < 0.05 and P = 0.07, respectively). At the molecular level, these adaptations in MHC IIA fibre function were explained by sex‐specific differences (P ≤ 0.05) in myosin–actin cross‐bridge kinetics. Additionally, cross‐bridge kinetics were slowed in MHC I fibres in OA patients (P < 0.01), attributable entirely to reductions in women with knee OA (P < 0.05), a phenotype that could be reproduced in vitro by chemical modification of protein thiol residues. Our results identify molecular and cellular functional adaptations in skeletal muscle that may contribute to reduced physical function with knee OA‐associated muscle disuse, with sex‐specific differences that may explain a greater disposition towards disability in women.

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Figures

Figure 1
Figure 1. Single skeletal muscle fibre force production, cross-sectional area (CSA) and tension (force/CSA)
Single muscle fibre force production, CSA and tension in myosin heavy chain (MHC) I, IIA and IIA/X fibres from healthy, active controls and volunteers with knee osteoarthritis (OA) in fibres evaluated for cellular contractile function. The number of fibres analysed in each group for each fibre type is indicated at the base of each bar on the top panel. Data were acquired under maximal Ca2+-activated conditions (pCa 4.5) at 15°C and represent means ± s.e.m. *P < 0.05; **P = 0.01.
Figure 2
Figure 2. Maximal shortening velocity, velocity and tension at which peak power is obtained and peak power output
Maximal shortening velocity (Vmax), velocity (Vopt) and tension (Topt) at which peak power is obtained and peak power output (Pmax), in myosin heavy chain (MHC) I, IIA and IIA/X fibres from healthy, active controls and volunteers with knee osteoarthritis (OA). Numbers of fibres analysed are identical to those in Fig. 1. Data were acquired under maximal Ca2+-activated conditions (pCa 4.5) at 15°C and represent means ± s.e.m.
Figure 3
Figure 3. Unloaded shortening velocity obtained from slack tests
Unloaded shortening velocity was obtained from slack tests conducted under maximal Ca2+-activated conditions (pCa 4.5) at 15°C in myosin heavy chain (MHC) I, IIA and IIA/X fibres from healthy, active controls and volunteers with knee osteoarthritis (OA). The number of fibres analysed in each group for each fibre type is indicated at the base of each bar. Data are means ± s.e.m.
Figure 4
Figure 4. Sex modifies the effects of osteoarthritis (OA) on myosin heavy chain (MHC) IIA contractile measurements
Influence of sex on the effects of OA on MHC IIA contractile measurements, including maximal power output (Pmax), maximal shortening velocity (Vmax) and velocity at which maximal power is obtained (Vopt) in healthy, active controls and volunteers with knee OA. The number of fibres analysed in each group for each fibre type is indicated at the base of each bar in the top panel. Data were acquired under maximal Ca2+-activated conditions (pCa 4.5) at 15°C and represent means ± s.e.m. *P ≤ 0.05; **P = 0.07 for group × sex effect.
Figure 5
Figure 5. Sinusoidal analysis parameters in myosin heavy chain (MHC) I, IIA and IIA/X fibres
Sinusoidal analysis parameters in MHC I, IIA and IIA/X fibres from healthy, active controls and volunteers with knee osteoarthritis (OA). Details of the physiological interpretation of each parameter are provided in Methods, under Molecular-level contractile function measurements. The number of fibres analysed in each group for each fibre type is indicated at the base of each bar in the top left panel. Functional data were acquired under maximal Ca2+-activated conditions (pCa 4.5) at 25°C. Data are means ± s.e.m. *P < 0.05; **P < 0.01.
Figure 6
Figure 6. Sex modifies the effects of osteoarthritis (OA) on sinusoidal analysis parameters
Effect of sex on OA effects on sinusoidal analysis parameters in myosin heavy chain (MHC) I and IIA fibres from healthy, active controls and volunteers with knee OA. The number of fibres analysed in each group is indicated at the base of each bar for each fibre type, with the middle and lower panel having the same number of fibres for the MHC IIA fibre type. Functional data were acquired under maximal Ca2+-activated conditions (pCa 4.5) at 25°C. Data are means ± s.e.m. *P ≤ 0.05; **P < 0.01; †P = 0.06.
Figure 7
Figure 7. Myosin and actin protein expression
Myosin and actin protein expression in tissue homogenates from the control (n = 14) and knee osteoarthritis (OA) (n = 16) groups. Data are means ± s.e.m.
Figure 8
Figure 8. Chemical modification of protein thiol residues with N-ethylmaleamide (NEM)
Effect of chemical modification of protein thiol residues with NEM on myosin attachment time and tension in myosin heavy chain (MHC) I fibres from control volunteers. Fibres were serially assessed for tension and myosin–actin cross-bridge kinetics before and following treatment with a single concentration of NEM. Numbers of fibres analysed under 0 μm, 12.5 μm, 25 μm and 50 μm were 9, 11, 6 and 5, respectively. The change in tension or ton at each NEM concentration is expressed relative to the change under control conditions (i.e. no NEM added). *P < 0.01 concentration-dependent effect of NEM.
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References

    1. Andersen JL, Gruschy-Knudsen T, Sandri C, Larsson L, Schiaffino S. Bed rest increases the amount of mismatched fibers in human skeletal muscle. J Appl Physiol. 1999;86:455–460. - PubMed
    1. Barreiro E, Coronell C, Laviña B, Ramírez-Sarmiento A, Orozco-Levi M, Gea J. Aging, sex differences, and oxidative stress in human respiratory and limb muscles. Free Radic Biol Med. 2006;41:797–809. - PubMed
    1. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833–1840. - PubMed
    1. Bottinelli R, Canepari M, Pellegrino MA, Reggiani C. Force-velocity properties of human skeletal muscle fibres: myosin heavy chain isoform and temperature dependence. J Physiol. 1996;495:573–586. - PMC - PubMed
    1. Cai D, Frantz JD, Tawa NE, Jr, Melendez PA, Oh B-C, Lidov HGW, Hasselgren P-O, Frontera WR, Lee J, Glass DJ, Shoelson SE. IKKβ/NF-κB activation causes severe muscle wasting in mice. Cell. 2004;119:285–298. - PubMed

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