Prolonged absence of myostatin reduces sarcopenia

Abstract

Sarcopenia is a progressive age-related loss of skeletal muscle mass and strength. Parabiotic experiments show that circulating factors positively influence the proliferation and regenerative capacity of satellite cells in aged mice. In addition, we believe that negative regulators of muscle mass also serve to balance the signals that influence satellite cell activation and regeneration capacity with ageing. Myostatin, a negative regulator of pre- and postnatal myogenesis, inhibits satellite cell activation and muscle regeneration postnatally. To investigate the role of myostatin during age-related sarcopenia, we examined muscle mass and regeneration in young and old myostatin-null mice. Young myostatin-null muscle fibers were characterized by massive hypertrophy and hyperplasia and an increase in type IIB fibers, resulting in a more glycolytic muscle. With ageing, wild-type muscle became increasingly oxidative and fiber atrophy was prominent. In contrast no fiber type switching was observed and atrophy was minimal in aged myostatin-null muscle. The effect of ageing on satellite cell numbers appeared minimal, however, satellite cell activation declined significantly in both wild-type and myostatin-null muscles. In young mice, lack of myostatin resulted in increased satellite cell number and activation compared to wild-type, suggesting a greater propensity to undergo myogenesis, a difference maintained in the aged mice. In addition, muscle regeneration of myostatin-null muscle following notexin injury was accelerated and fiber hypertrophy and type were recovered with regeneration, unlike in wild-type muscle. In conclusion, a lack of myostatin appears to reduce age-related sarcopenia and loss of muscle regenerative capacity.

Association of the K153R polymorphism in the myostatin gene and extreme longevity

“…In effect, myostatin is a skeletal muscle-specific secreted peptide that essentially modulates myoblast proliferation and thus muscle mass/strength . Preclinical trials using myostatin loss or inhibition have been effective in ameliorating symptoms of weakness in several animal Klimek et al 2010;Bogdanovich et al 2002;Lee and McPherron 2001;Liu et al 2008;Morrison et al 2009;Murphy et al 2010;Qiao et al 2009;Siriett et al 2006;Tsuchida 2008;Wagner et al 2008;Zhu et al 2007). In humans, myostatin inhibitors, such as MYO-029, have an adequate safety margin and are able to improve the muscle strength/function or muscle contractile properties in some patients with muscular dystrophy (Krivickas et al 2009;Wagner et al 2008).…”

“…Myostatin loss or inhibition has proven effective in ameliorating symptoms of weakness in several animal models of muscle injury, atrophy and disease (Benny Klimek et al 2010;Bogdanovich et al 2002;Lee and McPherron 2001;Liu et al 2008;Morrison et al 2009;Murphy et al 2010;Qiao et al 2009;Siriett et al 2006;Tsuchida 2008;Wagner et al 2008;Zhu et al 2007). Myostatin inhibition, as well as variations in the MSTN gene, can also have functional consequences in humans.…”

Genes and the ageing muscle: a review on genetic association studies

“…The myostatin-null mouse model also provides insights into the physiological role of this protein. Old myostatin-deficient mice have minimal muscle atrophy compared to their wild-type controls (Siriett et al 2006). It appears that myostatin also regulates the structure and function of tendon tissues, as the stiffness of tendons is 14 times higher in myostatin-deficient mice than in their wild-type controls (Mendias et al 2008).…”

The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan

“…It encodes myostatin, a skeletal muscle-specific secreted peptide that functions to limit muscle growth (McPherron et al 1997). In transgenic animal models, prolonged absence of myostatin reduces sarcopenia (Siriett et al 2006). Systemic treatment with myostatin inhibitors provides an adequate safety margin for clinical studies (Wagner et al 2008).…”