Sarcopenia, a critical loss of muscle mass and function because of the physiological process of aging, contributes to disability and mortality in older adults. It increases the incidence of pathologic fractures, causing prolonged periods of hospitalization and rehabilitation. The molecular mechanisms underlying sarcopenia are poorly understood, but recent evidence suggests that increased transforming growth factor–β (TGF-β) signaling contributes to impaired satellite cell function and muscle repair in aged skeletal muscle. We therefore evaluated whether antagonism of TGF-β signaling via losartan, an angiotensin II receptor antagonist commonly used to treat high blood pressure, had a beneficial impact on the muscle remodeling process of sarcopenic mice. We demonstrated that mice treated with losartan developed significantly less fibrosis and exhibited improved in vivo muscle function after cardiotoxin-induced injury. We found that losartan not only blunted the canonical TGF-β signaling cascade but also modulated the noncanonical TGF-β mitogen-activated protein kinase pathway. We next assessed whether losartan was able to combat disuse atrophy in aged mice that were subjected to hindlimb immobilization. We showed that immobilized mice treated with losartan were protected against loss of muscle mass. Unexpectedly, this protective mechanism was not mediated by TGF-β signaling but was due to an increased activation of the insulin-like growth factor 1 (IGF-1)/Akt/mammalian target of rapamycin (mTOR) pathway. Thus, blockade of the AT1 (angiotensin II type I) receptor improved muscle remodeling and protected against disuse atrophy by differentially regulating the TGF-β and IGF-1/Akt/mTOR signaling cascades, two pathways critical for skeletal muscle homeostasis. Thus, losartan, a Food and Drug Administration–approved drug, may prove to have clinical benefits to combat injury-related muscle remodeling and provide protection against disuse atrophy in humans with sarcopenia.

Maintaining skeletal muscle mass is essential for general health and prevention of disease progression in various neuromuscular conditions. Currently, no treatments are available to prevent progressive loss of muscle mass in any of these conditions. Hibernating mammals are protected from muscle atrophy despite prolonged periods of immobilization and starvation. Here, we describe a mechanism underlying muscle preservation and translate it to non-hibernating mammals. Although Akt has an established role in skeletal muscle homeostasis, we find that serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates muscle mass maintenance via downregulation of proteolysis and autophagy as well as increased protein synthesis during hibernation. We demonstrate that SGK1 is critical for the maintenance of skeletal muscle homeostasis and function in non-hibernating mammals in normal and atrophic conditions such as starvation and immobilization. Our results identify a novel therapeutic target to combat loss of skeletal muscle mass associated with muscle degeneration and atrophy.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of Parkinson's disease (PD). Whether loss of LRRK2 function accounts for neurodegeneration of dopamine neurons in PD is not known, nor is it known whether LRRK2 kinase activity modulates the susceptibility of dopamine (DA) neurons to the selective dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To better understand the role of LRRK2 in DA neuronal survival and its role in the susceptibility of DA neurons to MPTP, we generated LRRK2 knock-out (KO) mice lacking the kinase domain of LRRK2. Here, we show that LRRK2 KO mice are viable and have no major abnormalities and live to adulthood. The dopaminergic system is normal in LRRK2 KO mice as assessed via HPLC for DA and its metabolites and via stereologic assessment of DA neuron number in young and aged mice. Importantly, there is no significant difference in the susceptibility of LRRK2 KO and wild-type mice to MPTP. These results suggest that LRRK2 plays little if any role in the development and survival of DA neurons under physiologic conditions. Thus, PD due to LRRK2 mutations are likely not due to a loss of function. Moreover, LRRK2 is not required for the susceptibility of DA neurons to MPTP. IntroductionProgressive and selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is one of the main neuropathological findings in Parkinson's disease (PD). Although PD is mostly a sporadic disorder and the etiology is not known, its pathogenesis may involve genetic susceptibility and environmental factors, that will cause oxidative stress, impairments in mitochondria and the proteosome, or aggregation of misfolded proteins (Dawson and Dawson, 2003;Vila and Przedborski, 2004;Moore et al., 2005).Only a 10% of the PD cases are linked to Mendelian genetic defects, and mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent of the familial forms of PD (Gasser, 2007;Lees et al., 2009). Several missense mutations distributed along the protein have been reported, but the role of LRRK2 in the pathophysiology of PD is still not well known. The kinase activity may be a link between LRRK2 and PD West et al., , 2007 as attenuation of LRRK2 kinase activity prevents LRRK2 toxicity in cellular models of PD. LRRK2 also has independent GTPase activity that can regulate its kinase activity (Greggio et al., 2008). It is assumed that LRRK2 mutations linked to PD are gain of function mutations in which the kinase domain is critical for the toxic actions of mutant LRRK2 (Biskup and West, 2009).Previous studies showed that LRRK2 is associated with the mitochondria (Biskup et al., 2006), and that the toxicity mediated by LRRK2 mutants could be due to mitochondria-dependent apoptosis (Iaccarino et al., 2007). Wild-type (WT) LRRK2, but not the mutants, attenuate hydrogen peroxide (H 2 O 2 )-induced oxidative stress suggesting a protective role for LRRK2 (Liou et al., 2008). Moreover, data generated in lines of Caenorhabditis elegans express...