Abstract
Sarcopenia, a loss of muscle mass and functionality, constitutes a major contributor to disability in diabetes. Hydrogen sulfide (H2S) dynamics and muscle mass regulatory signaling were studied in GK rats, a model for type 2 diabetes (T2D). GK rats exhibited a number of features that are consistent with sarcopenia and T2D including loss of muscle mass and strength, in addition to glucose intolerance, insulin resistance, and impaired β-cell responsiveness to glucose. Mechanistically, activation levels of Akt, a key modulator of protein balance, were decreased in T2D. Consequently, we confirmed reduced activity of mTOR signaling components and higher expression of atrophy-related markers typified by FoxO1/atrogin-1/MuRF1 and myostatin-Smad2/3 signaling during the course of diabetes. We observed in GK rat reduced antioxidant capacity (↓GSH/GSSG) and increased expression and activity of NADPH oxidase in connection with augmented rate of oxidation of lipids, proteins, and DNA. H2S bioavailability and the expression of key enzymes involved in its synthesis were suppressed as a function of diabetes. Interestingly, GK rats receiving NaHS displayed increased muscle Akt/mTOR signaling and decreased expression of myostatin and the FoxO1/MuRF1/atrogin-dependent pathway. Moreover, diabetes-induced heightened state of oxidative stress was also ameliorated in response to NaHS therapy. Overall, the current data support the notion that a relationship exists between sarcopenia, heightened state of oxidative stress, and H2S deficiency at least in the context of diabetes. Moreover, treatment with a potent H2S donor at an early stage of diabetes is likely to mitigate the development of sarcopenia/frailty and predictably reduces its devastating sequelae of amputation.
Highlights
Sarcopenia, a loss of muscle mass and function, is one of the most dramatic phenotypic changes during the course of advanced aging [1, 2] and diabetes
We measured in Goto Kakizaki (GK) rats key indices of sarcopenic symptoms with the resulting data revealing a significant reduction in the mass of both gastrocnemius and soleus muscles, even when the data were expressed as a function of body weight (Figures 1(d) and 1(e))
To determine whether the changes in muscle mass correlates with muscle functionality, a grip strength test was applied on various groups of animals
Summary
Sarcopenia, a loss of muscle mass and function, is one of the most dramatic phenotypic changes during the course of advanced aging [1, 2] and diabetes. Recent data indicated that sarcopenia is an important prognostic factor for critical limb ischemia (CLI) [4]. The latter phenomenon is a manifestation of peripheral arterial disease, affecting nearly 2 million people in United States, and it is usually described in terms of chronic ischemic rest pain or ischemic skin lesions with either ulcers or gangrene [5, 6]. Patients with CLI and diabetes have poor prognosis in connection with severe atherosclerotic lesions and high risk of amputation [7,8,9,10,11].
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