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Disorders of the Skeletal Muscle01:28

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The clinical conditions affecting the skeletal muscle tissue are broadly categorized as musculoskeletal and neuromuscular disorders.
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As muscle contracts, the overlap between the thin and thick filaments increases, decreasing the length of the sarcomere—the contractile unit of the muscle—using energy in the form of ATP. At the molecular level, this is a cyclic, multistep process that involves binding and hydrolysis of ATP, and movement of actin by myosin.
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Skeletal muscle relaxants are widely used for muscle paralysis and relieving pain following any muscle injury or stiffness. However, depending on the drug type, they can have adverse effects that range from mild to severe. Usually, nondepolarizing neuromuscular blockers have minimal side effects. For example, drugs like d-tubocurarine, cisatracurium, and rocuronium cause hypotension, whereas drugs like baclofen, when stopped abruptly, can lead to the recurrence of spastic conditions.
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Klotho Deficiency Promotes Skeletal Muscle Weakness and Is Associated with Impaired Motor Unit Connectivity.

Linda A Bean1, Connor Thomas1, Juan F Villa1,2

  • 1Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

International Journal of Molecular Sciences
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Summary

Systemic Klotho deficiency causes muscle wasting and weakness by disrupting neuromuscular junctions and motor unit connectivity. This study reveals Klotho

Keywords:
Klothomotor unitskeletal musclewasting

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Area of Science:

  • Muscle physiology and molecular biology
  • Aging and regenerative medicine
  • Neuromuscular disorders

Background:

  • Muscle wasting and weakness significantly impact mobility, independence, and overall health.
  • Reduced Klotho expression is observed in aging, chronic kidney disease, and myopathy, conditions linked to muscle wasting.

Purpose of the Study:

  • To investigate the mechanistic role of Klotho in regulating muscle wasting and weakness.
  • To elucidate how Klotho deficiency affects muscle structure, function, and innervation.

Main Methods:

  • Comparative analysis of Klotho-deficient (null) mice and controls.
  • Assessment of body composition, muscle mass, myofiber characteristics, and enzymatic activity.
  • Evaluation of muscle contractility using force and torque measurements.
  • RNA sequencing to analyze gene expression changes in muscle.
  • Histological examination of neuromuscular junctions and motor units.

Main Results:

  • Klotho deficiency led to reduced body weight, lean mass, muscle mass, and myofiber size.
  • Klotho-null mice exhibited impaired muscle contractility, with decreased twitch force and torque.
  • Analysis revealed neuromuscular junction remodeling, myofiber denervation, and loss of functional motor units.
  • Increased glycolytic GPDH activity and altered myofiber type composition (more IIb, fewer IIx) were observed.

Conclusions:

  • Systemic Klotho deficiency disrupts muscle synapses and motor unit connectivity.
  • Klotho plays a critical role in maintaining neuromuscular integrity and muscle function.
  • These findings suggest a novel mechanism linking Klotho to muscle wasting and weakness.