Table 2.

Summary of contractile mechanics studies on nebulin deficient or nebulin mutant muscle

Model/muscle type/age	Experimental setup	SL (μm)	Finding						Publication
			Specific force deficit (% of WT)	kTR	Tension cost	Force/Ca2+ curve	Active stiffness	Other
Neb KO mice/TA/P1	Intact muscle mechanics	N/A	50%	N/D	N/D	N/D	N/D	Reduced thin filament length, excitation/contraction coupling was not significantly altered, at this age the contractile machinery displayed normal morphology	Bang et al. (2006)
Neb KO mice/TA/P10	Permeabilized fiber bundle contractility	2	N/D?	N/D	N/D	pCa50 – nH ↓	N/D		Witt et al. (2006)
Neb KO mice/gastrocnemius/P1 and P7	Intact muscle mechanics	N/A	P1 = 73% P7 = 8%	N/D	N/D	N/D	N/D	Force–SL relationship was shifted to the left, greater force decline during repeated isometric tetani	Gokhin et al. (2009)
Neb KO mice/Psoas/P1	Permeabilized fiber bundle contractility thin filament length and structure were comparable to control	2.6	35%	↓	N/D	pCa50 – nH –	↓	Tension/stiffness was normal, conclusion: reduction in the number of motors without affecting the force per motor due to reduced attachment rate	Bang et al. (2009)
Neb KO mice/TA/P7-9	Permeabilized fiber bundle contractility; at SL of 2.0 µm both, WT and KO fibers, are predicted to produce 80% of WT Fmax	2.0	~ 50%	↓	↑	pCa50 ↓ nH ↓	↓	Tension/stiffness was normal, no changes in myosin heavy chain isoforms, myosin light chain composition/phosphorylation and troponin and tropomyosin isoforms conclusion: reduction in the number of motors without affecting the force per motor, nebulin has a direct role in modulating calcium sensitivity of the thin filament	Chandra et al. (2009)
4 NEB-NM patients	Permeabilised fiber bundles contractility	2.5 (Control), just above slack in NEB myofibers	7%	↓	↑	pCa50 ↓ nH –	N/D	Reduced thin filament length	Ottenheijm et al. (2010)
1 NEB-NM patient	Permeabilised fiber bundles contractility	2.5 (Control), just above slack in NEB myofibers	5%	↓	↑	N/D	N/D		Lawlor et al. (2011)
1 NEB-NM patient	Permeabilized fibre contractility	2.70–2.80	69%	↓	N/D	pCa50 – nH –	↓	Normal force–sarcomere length relationship, abnormal myosin light chain composition, tension/stiffness was normal	Ochala et al. (2011)
								Conclusion: reduction in the fraction of myosin heads strongly bound to actin rather than a decrease in the force per myosin cross-bridge
NebΔ55 mice/TA/P4-7	Permeabilized fibre contractility and individual myofibrils, sarcomere length?	2.2	38% (At SL of 2.4 µm)	↓	↑	pCa50 ↓ nH –	N/D	Force–SL relationship was shifted to the left	Ottenheijm et al. (2013)
4 NEB-NM patients	Permeabilised fiber bundle contractility	2.1 and 2.6	17%	N/D	N/D	SL 2.1 pCa50 ↓ nH ↓ SL 2.6 pCa50 – nH N/D	N/D		de Winter et al. (2013)
NebΔSH3 mouse, EDL (2m, 6m)	Intact muscle mechanics	N/A	100%	N/D	N/D	N/D	N/D	More force loss due to eccentric contractions, less sensitive to electrical stimulation (force/frequency)	Yamamoto et al. (2013)
Neb cKO mice soleus, EDL (5w and 6m)	Exercise testing, intact muscle mechanics permeabilized fiber/fiber bundles contractility	2.4	SOLintact (5w) 58%	↓	↑	N/D	↓	Tension/stiffness was normal, reduced exercise performance, reduced thin filament length, reduced fraction of strongly attached cross-bridges	Li et al. (2015)
			SOLintact (6m) 43%
			EDLintact (5w) 15%
			EDLintact (6m) 23%
			SOLperm?
			EDLperm?
NebΔ55 mice (6d)/diaphragm, soleus, EDL, gastrocnemius	Permeabilized fibre and individual myofibril contractility	2.3	40–24%	↓	N/D	pCa50 ↓ nH –	↓	Tension/stiffness was normal, Conclusion: reduction in the number of motors without affecting the force per motor	Joureau et al. (2017)
Neb cKO/soleus	Permeabilised fiber bundle contractility	2.5	52%	N/D	N/D	N/D	↓	Ratio active stiffness/rigor stiffness was comparable to wild type	Kawai et al. (2018)
								Conclusion: equal amount of cross-bridges are activated during contraction
NebΔ163–165	Intact muscle mechanics	N/A	A slight force deficit was observed in soleus, while a drastic loss of force was present in EDL	N/D	N/D	N/D	N/D	More force loss due to eccentric contractions, no change in sensitivity to electrical stimulation (force/frequency)	Li et al. (2019)

TA Tibialis Anterior, KO knock out, WT wild type, NM nemaline myopathy, N/D no data, N/A not applicable, EDL extensor digitorum longus, SL sarcomere length; ↓, ↑, – down-regulation, up-regulation, unchanged (compared to wild-type), respectively, Fmax tension at saturating Ca²⁺