Overexpression of HSP10 in skeletal muscle of transgenic mice prevents the age-related fall in maximum tetanic force generation and muscle cross-sectional area

Abstract

Kayani AC, Close GL, Dillmann WH, Mestril R, Jackson MJ, McArdle A. Overexpression of HSP10 in skeletal muscle of transgenic mice prevents the age-related fall in maximum tetanic force generation and muscle cross-sectional area. Am J Physiol Regul Integr Comp Physiol 299: R268 -R276, 2010. First published April 21, 2010 doi:10.1152/ajpregu.00334.2009.-Skeletal muscle atrophy and weakness are major contributors to frailty and impact significantly on quality of life of older people. Muscle aging is characterized by a loss of maximum tetanic force (Po) generation, primarily due to muscle atrophy, to which mitochondrial dysfunction is hypothesized to contribute. We hypothesized that lifelong overexpression of the mitochondrial heat shock protein (HSP) HSP10 in muscle of mice would protect against development of these deficits. Po generation by extensor digitorum longus muscles of adult and old wild-type and HSP10-overexpressing mice was determined in situ. Muscles were subjected to damaging lengthening contractions, and force generation was remeasured at 3 h or 28 days to examine susceptibility to, and recovery from, damage, respectively. Muscles of old wild-type mice had a 23% deficit in Po generation and a 10% deficit in muscle cross-sectional area compared with muscles of adult wild-type mice. Overexpression of HSP10 prevented this age-related fall in Po generation and reduction in cross-sectional area observed in muscles of old wild-type mice. Additionally, overexpression of HSP10 protected against contraction-induced damage independent of age but did not improve recovery if damage occurred. Preservation of muscle force generation and CSA by HSP10 overexpression was associated with protection against the age-related accumulation of protein carbonyls. Data demonstrate that development of age-related muscle weakness may not be inevitable and show, for the first time, that lifelong overexpression of an HSP prevents the age-related loss of P o generation. These findings support the hypothesis that mitochondrial dysfunction is involved in the development of age-related muscle deficits.aging; heat shock protein; Cpn10; Hspe1; atrophy SKELETAL MUSCLE FUNCTION DECLINES significantly with age and is characterized by the loss of maximum tetanic force (P o ) generation and muscle cross-sectional area (CSA) (5,21,27). The development of these functional deficits has been hypothesized to result from the increased susceptibility of muscles to, and incomplete recovery from, contraction-induced damage (14). The mechanism(s) responsible for this is unclear, although a failure in the ability to activate the stress or heat shock response has been implicated. The heat shock protein (HSP) content of skeletal muscle of adult mammals is increased following short-and long-term exercise protocols (23, 37). In contrast, the HSP content and the ability to activate a stress response are modified in skeletal muscle with age; this has also been proposed to play a role in the development of age-related muscle deficits (35).HSPs are molecular...

Frailty and sarcopenia as the basis for the phenotypic manifestation of chronic diseases in older adults

“…Supportive of this, decreased production of HSPs in response to contractile stimulus was observed in muscles derived from old mice when compared to adult mice (Vasilaki et al, 2006b). This latter may play a critical role in the development of functional decline that occur with aging in skeletal muscle since overexpression of HSP10 (mitochondrial chaperone protein) was shown to preserve muscle function in aged transgenic mice (Kayani et al, 2010).…”

Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models

“…In mice, overexpression of the mitochondrial chaperone Hsp10 in skeletal muscle prevents age-related decline in muscle mass and strength (Kayani et al, 2010), providing further evidence that the UPR mt is a protective response to sarcopenia. Moreover, analyses of mice with a reporter based on Xbp1 mRNA splicing indicated that muscle aging is also characterized by the induction of the unfolded protein response in the endoplasmic reticulum (UPR ER ) (Iwawaki et al, 2004).…”

Role of reactive oxygen species in the defective regeneration seen in aging muscle

“…Studies using transgenic mice overexpressing HSP70 have shown that increased muscle content of HSP70 provided protection against the fall in specific force associated with aging, and facilitated rapid and successful regeneration following contraction-induced damage in muscles of old HSP70 overexpressor mice compared with the impaired regeneration and recovery normally observed in old wild type mice [16]. More recently, we have also demonstrated that overexpression of HSP10, a mitochondrial chaperone protein, can also preserve muscle function during aging in mice [61]. …”