The purpose of this study was to determine if PKB signaling is decreased and contractile protein degradation is increased in extensor digitorum longus (EDL) and soleus (SOL) muscles from middle-aged (MA) and aged (AG) mice. We also examined the effect of age on atrogene expression in quadriceps muscle. PKB activity, as assessed by Thr(308) and Ser(473) phosphorylation, was significantly higher in EDL and SOL muscles from AG than MA mice. The age-related increase in PKB activity appears to be due to an increase in expression of the kinase, as PKB-α and PKB-β levels were significantly higher in EDL and SOL muscles from AG than MA mice. The phosphorylation of forkhead box 3a (FOXO3a) on Thr(32), a PKB target, was significantly higher in EDL muscles from AG than MA mice. The rate of contractile protein degradation was similar in EDL and SOL muscles from AG and MA mice. Atrogin-1 and muscle-specific RING finger protein 1 (MuRF-1) mRNA levels did not change in muscles from AG compared with MA mice, indicating that ubiquitin-proteasome proteolysis does not contribute to sarcopenia. A significant decrease in Bcl-2 and 19-kDa interacting protein 3 (Bnip3) and GABA receptor-associated protein 1 (Gabarap1) mRNA was observed in muscles from AG compared with MA mice, which may contribute to age-related contractile dysfunction. In conclusion, the mechanisms responsible for sarcopenia are distinct from experimental models of atrophy and do not involve atrogin-1 and MuRF-1 or enhanced proteolysis. Finally, a decline in autophagy-related gene expression may provide a novel mechanism for impaired contractile function and muscle metabolism with advancing age.
"Intriguingly, overexpression of the FOXO increases the expression of many autophagy genes, preserves the function of the autophagy pathway, and prevents the accumulation of polyubiquitin protein aggregates in sarcopenic Drosophila muscle (Demontis and Perrimon, 2009). Several investigators reported the autophagic changes in aged mammalian skeletal muscle (McMullen et al., 2009; Wenz et al., 2009; Wohlgemuth et al., 2010; Gaugler et al., 2011). Compared with those in young male Fischer 344 rats, amounts of Beclin-1 were significantly increased in the plantaris muscles of senescent rats (Wohlgemuth et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This review provides an overview of the adaptive changes in several regulators of muscle mass in both sarcopenia and muscular dystrophy.
"Conflicting results have been observed in the age-related mRNA regulation of MURF1 and atrogin-1 (FBXO32), suggestive of gender, muscle type and species influences (rodent vs. human muscle). Compared to younger rodent muscle, studies have shown that baseline MURF1 and atrogin-1 mRNA levels in aged rodents increase in the tibialis anterior (Clavel et al., 2006), decrease in the gastrocnemius muscle (Edstrom et al., 2006) or do not differ in the extensor digitorum longus and soleus muscle (Gaugler et al., 2011). In humans, some studies find an increase in MURF1 baseline mRNA expression in older muscle compared to younger muscle (Raue et al., 2007; Dalbo et al., 2011; Merritt et al., 2013), while other groups report no differences (Welle et al., 2003; Whitman et al., 2005; Léger et al., 2008; Greig et al., 2011; Fry et al., 2013) Albeit one study showing a subtle elevation in baseline atrogin-1 mRNA expression with ageing (Merritt et al., 2013), age-related differences in basal atrogin-1 mRNA expression do not occur (Welle et al., 2003; Whitman et al., 2005; Raue et al., 2007; Léger et al., 2008; Dalbo et al., 2011; Greig et al., 2011; Fry et al., 2013; Sandri et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Skeletal muscle atrophy is a critical component of the ageing process. Age-related muscle wasting is due to disrupted muscle protein turnover, a process mediated in part by the ubiquitin proteasome pathway (UPP). Additionally, older subjects have been observed to have an attenuated anabolic response, at both the molecular and physiological levels, following a single-bout of resistance exercise (RE). We investigated the expression levels of the UPP-related genes and proteins involved in muscle protein degradation in 10 older (60-75 years) vs. 10 younger (18-30 years) healthy male subjects at basal as well as 2 h after a single-bout of RE. MURF1, atrogin-1 and FBXO40, their substrate targets PKM2, myogenin, MYOD, MHC and EIF3F as well as MURF1 and atrogin-1 transcriptional regulators FOXO1 and FOXO3 gene and/or protein expression levels were measured via real time PCR and western blotting, respectively. At basal, no age-related difference was observed in the gene/protein levels of atrogin-1, MURF1, myogenin, MYOD and FOXO1/3. However, a decrease in FBXO40 mRNA and protein levels was observed in older subjects, while PKM2 protein was increased. In response to RE, MURF1, atrogin-1 and FBXO40 mRNA were upregulated in both the younger and older subjects, with changes observed in protein levels. In conclusion, UPP-related gene/protein expression is comparably regulated in healthy young and old male subjects at basal and following RE. These findings suggest that UPP signaling plays a limited role in the process of age-related muscle wasting. Future studies are required to investigate additional proteolytic mechanisms in conjunction with skeletal muscle protein breakdown (MPB) measurements following RE in older vs. younger subjects.
Frontiers in Physiology 01/2014; 5:30. DOI:10.3389/fphys.2014.00030 · 3.53 Impact Factor
"Despite the initial protection that stress responses can confer, they are a potential cause of muscle deterioration if excessive. In the muscles of old rats, there seems to be a prolonged decrease in protein synthesis and increase in protein degradation via the UPS, all of which might initially compensate for the accumulation of damaged proteins during aging (Clavel et al., 2006; Gaugler et al., 2011; Ludatscher et al., 1983; Wohlgemuth et al., 2010). However, excessive induction of some of these stress responses, including JNK signaling and UPS activity, is known to be deleterious and, in muscle, could promote degradation of functional myofibrillar proteins, lead to the loss of muscle bulk and trigger apoptosis. "
[Show abstract][Hide abstract] ABSTRACT: A characteristic feature of aged humans and other mammals is the debilitating, progressive loss of skeletal muscle function and mass that is known as sarcopenia. Age-related muscle dysfunction occurs to an even greater extent during the relatively short lifespan of the fruit fly Drosophila melanogaster. Studies in model organisms indicate that sarcopenia is driven by a combination of muscle tissue extrinsic and intrinsic factors, and that it fundamentally differs from the rapid atrophy of muscles observed following disuse and fasting. Extrinsic changes in innervation, stem cell function and endocrine regulation of muscle homeostasis contribute to muscle aging. In addition, organelle dysfunction and compromised protein homeostasis are among the primary intrinsic causes. Some of these age-related changes can in turn contribute to the induction of compensatory stress responses that have a protective role during muscle aging. In this Review, we outline how studies in Drosophila and mammalian model organisms can each provide distinct advantages to facilitate the understanding of this complex multifactorial condition and how they can be used to identify suitable therapies.
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