Principal Investigator, TIGEM
Associate Professor of General Pathology, Department of Biomedical Science, University of Padova, Italy
Signaling pathways that control protein and organelle homeostasis in muscles
Cardiac and skeletal muscles adapt their masses in response to physical activity, metabolism and hormones. Inherited disorders, inactivity and catabolic conditions, such as cancer, diabetes, AIDS and chronic heart failure induce signaling pathways that regulate the process of muscle loss. Shrinkage of muscle cells in adult tissue, known otherwise as atrophy, and the consequent weakness occur when rates of protein degradation exceed that of protein synthesis. Two major protein degradation pathways, the ubiquitin-proteasome and the autophagy-lysosome systems, are activated during muscle atrophy and variably contribute to the loss of muscle mass.
Our findings have contributed to the identification of the mechanisms that regulate these proteolytic systems. Indeed, we were the first to show that a transcription-dependent program that modulates the expression of rate-limiting enzymes modulates the ubiquitin-proteasome system (Sandri et al. Cell, 2004). FoxO transcription factors, which are negatively regulated by the Insulin-Akt pathway, were the first proteins to be considered critical for regulating the atrophy process. We then found that the FoxO family activates ubiquitin-proteasome and autophagy-lysosome pathways to remove proteins and organelles in atrophying muscle tissue (Mammucari et al. Cell Metab. 2007). However, these proteolytic systems also prevent the accumulation of damaged proteins and dysfunctional organelles. Given their important role in protein and organelle quality control, these degradation pathways need to be carefully regulated. Indeed, we have found that either excessive or defective autophagy-lysosome or ubiquitin-proteasome activity leads to detrimental effects on muscle homeostasis and function (Masiero et al. Cell Metab. 2009; Sartori et al. Nat. Genet. 2013). This also happens in inherited muscle disorders. Indeed we have found that autophagy was impaired in different muscular dystrophy conditions, such as Duchenne and collagen VI deficiency (Grumati et al. Nat. Med. 2010). Moreover, we also showed that restoring normal autophagy flux in these dystrophies via genetic, pharmacological or nutritional approaches was sufficient to ameliorate muscle function and retard disease progression. Altogether these findings introduce the concept that protein homeostasis is carefully regulated at multiple levels, and that disruption or abnormalities in its control contribute to the etiopathogenesis of inherited and acquired diseases.
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL (2004). Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 117, 399-412. doi:10.1016/S0092-8674(04)00400-3.
Mammucari C, Milan G, Romanello V, Masiero E, Ruediger R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007). FoxO3 controls autophagy in skeletal muscle in vivo.Cell Metab.6(6):458-71.
Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M (2009). Autophagy is required to maintain muscle mass. Cell Metab. 10(6):507-15. doi: 10.1016/j.cmet.2009.10.008.
Grumati P*, Coletto L*, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M#, Bonaldo P# (2010). Autophagy is defective in collagen VI muscular dystrophies and its reactivation rescues myofiber degeneration. Nat Med. 16(11):1313-20. doi: 10.1038/nm.2247.
Sartori R, Schirwis E, Blaauw B, Bortolanza S, Zhao J, Enzo E, Stantzou A, Mouisel E, Toniolo L, Ferry A, Stricker S, Goldberg AL, Dupont S, Piccolo S, Amthor H, Sandri M (2013). BMP signaling controls muscle mass. Nat Genet. 45(11):1309-18. doi:10.1038/ng.2772.
Zaglia T, Milan G, Ruhs A, Franzoso M, Bertaggia E, Pianca N, Carpi A, Carullo P, Pesce P, Sacerdoti D, Sarais C, Catalucci D, Krüger M, Mongillo M, Sandri M (2014). Atrogin-1/MAFbx impairs CHMP2B turnover blocks autophagy flux and causes cardiomyopathy. J Clin Invest. 124(6):2410-24. doi: 10.1172/JCI66339.
Carnio S, LoVerso F, BaraibarMA, Longa E, Khan MM, Maffei M, Reischl M, Canepari M, Loefler S, Kern H, Blaauw B, Friguet B, Bottinelli R, Rudolf R, Sandri M (2014). Impairment of autophagy in muscle induces neuro-muscular junction degeneration and precocious aging. Cell Reports. 8(5):1509-21. doI: 10.1016/j.celrep.2014.07.061.