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Neuromuscular electrical stimulation promotes development in mice of mature human muscle from immortalized human myoblasts.

ABSTRACT: Studies of the pathogenic mechanisms underlying human myopathies and muscular dystrophies often require animal models, but models of some human diseases are not yet available. Methods to promote the engraftment and development of myogenic cells from individuals with such diseases in mice would accelerate such studies and also provide a useful tool for testing therapeutics. Here, we investigate the ability of immortalized human myogenic precursor cells (hMPCs) to form mature human myofibers following implantation into the hindlimbs of non-obese diabetic-Rag1 (null) IL2rγ (null) (NOD-Rag)-immunodeficient mice.We report that hindlimbs of NOD-Rag mice that are X-irradiated, treated with cardiotoxin, and then injected with immortalized control hMPCs or hMPCs from an individual with facioscapulohumeral muscular dystrophy (FSHD) develop mature human myofibers. Furthermore, intermittent neuromuscular electrical stimulation (iNMES) of the peroneal nerve of the engrafted limb enhances the development of mature fibers in the grafts formed by both immortal cell lines. With control cells, iNMES increases the number and size of the human myofibers that form and promotes closer fiber-to-fiber packing. The human myofibers in the graft are innervated, fully differentiated, and minimally contaminated with murine myonuclei.Our results indicate that control and FSHD human myofibers can form in mice engrafted with hMPCs and that iNMES enhances engraftment and subsequent development of mature human muscle.

SUBMITTER: Sakellariou P

PROVIDER: S-EPMC4769538 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Project description:Muscle-tendon unit length plays a crucial role in quadriceps femoris muscle (QF) physiological adaptation, but the influence of hip and knee angles during QF neuromuscular electrical stimulation (NMES) is poorly investigated. We investigated the effect of muscle length on maximum electrically induced contraction (MEIC) and current efficiency. We secondarily assessed the architecture of all QF constituents and their tendon-aponeurosis complex (TAC) displacement to calculate a stiffness index. This study was a randomized, repeated measure, blinded design with a sample of twenty healthy men aged 24.0 ± 4.6. The MEIC was assessed in four different positions: supine with knee flexion of 60° (SUP60); seated with knee flexion of 60° (SIT60); supine with knee flexion of 20° (SUP20), and seated with knee flexion of 20° (SIT20). The current efficiency (MEIC/maximum tolerated current amplitude) was calculated. Ultrasonography of the QF was performed at rest and during NMES to measure pennation angle (θ p ) and fascicle length (L f ), and the TAC stiffness index. MEIC and current efficiency were greater for SUP60 and SIT60 compared to SUP20 and SIT20. The vastus lateralis and medialis showed lower θ p and higher L f at SUP60 and SIT60, while for the rectus femoris, in SUP60 there were lower θ p and higher L f than in all positions. The vastus intermedius had a similar pattern to the other vastii, except for lack of difference in θ p between SIT60 compared to SUP20 and SIT20. The TAC stiffness index was greater for SUP60. We concluded that NMES generate greater torque and current efficiency at 60° of knee flexion, compared to 20°. For these knee angles, lengthening the QF at the hip did not promote significant change. Each QF constituent demonstrated muscle physiology patterns according to hip and/or knee angles, even though a greater L f and lower θ p were predominant in SUP60 and SIT60. QF TAC index stiffened in more elongated positions, which probably contributed to enhanced force transmission and slightly higher torque in SUP60. Our findings may help exercise physiologist better understand the impact of hip and knee angles on designing more rational NMES stimulation strategies.Clinical trial registrationwww.ClinicalTrials.gov, identifier NCT03822221.

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Neuromuscular electrical stimulation promotes development in mice of mature human muscle from immortalized human myoblasts.

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