Reduced skeletal muscle phosphocreatine concentration in type 2 diabetic patients: a quantitative image-based phosphorus-31 MR spectroscopy study

Abstract

Mitochondrial function has been examined in insulin-resistant (IR) states including type 2 diabetes mellitus (T2DM). Previous studies using phosphorus-31 magnetic resonance spectroscopy (P-MRS) in T2DM reported results as relative concentrations of metabolite ratios, which could obscure differences in phosphocreatine ([PCr]) and adenosine triphosphate concentrations ([ATP]) between T2DM and normal glucose tolerance (NGT) individuals. We used an image-guided P-MRS method to quantitate [PCr], inorganic phosphate [Pi], phosphodiester [PDE], and [ATP] in vastus lateralis (VL) muscle in 11 T2DM and 14 NGT subjects. Subjects also received oral glucose tolerance test, euglycemic insulin clamp, H-MRS to measure intramyocellular lipids [IMCL], and VL muscle biopsy to evaluate mitochondrial density. T2DM subjects had lower absolute [PCr] and [ATP] than NGT subjects (PCr 28.6 ± 3.2 vs. 24.6 ± 2.4, P< 0.002, and ATP 7.18 ± 0.6 vs. 6.37 ± 1.1, P < 0.02) while [PDE] was higher, but not significantly. [PCr], obtained using the traditional ratio method, showed no significant difference between groups. [PCr] was negatively correlated with HbA1c ( r = -0.63, P < 0.01) and fasting plasma glucose ( r = -0.51, P = 0.01). [PDE] was negatively correlated with Matsuda index ( r = -0.43, P = 0.03) and M/I ( r = -0.46, P = 0.04), but was positively correlated with [IMCL] ( r = 0.64, P < 0.005), HbA1c, and FPG ( r = 0.60, P = 0.001). To summarize, using a modified, in vivo quantitative P-MRS method, skeletal muscle [PCr] and [ATP] are reduced in T2DM, while this difference was not observed with the traditional ratio method. The strong inverse correlation between [PCr] vs. HbA1c, FPG, and insulin sensitivity supports the concept that lower baseline skeletal muscle [PCr] is related to key determinants of glucose homeostasis.

Older adults with sarcopenia have distinct skeletal muscle phosphodiester, phosphocreatine, and phospholipid profiles

“…These participants, while all obese, had a wide range in muscle mass markers (skeletal muscle index [SMI]: 6.2–11.0 ALM/hr 2 ; muscle volume: 1,073.1–2,709.4 cm 3 ) as well as muscle functionality (peak power: 25.0–227.8 W). Despite other reports linking phosphorus metabolites with insulin sensitivity (Ripley et al, 2018; Szendroedi et al, 2011), we found that type 2 diabetes status did not influence the in vivo metabolic phenotype (data not shown), and therefore, all subjects were grouped for correlative analyses. Next, we examined relationships with body composition measurements and found that SMI, an index of muscle mass used to define sarcopenic status, was associated with two metabolites, PCr ( r = .365; p ‐value = .008) and PDE2 ( r = −0.366; p ‐value = .008).…”

“…Though not as well studied, recent evidence has revealed that resting in vivo phosphorus metabolite levels may relate to whole‐body and muscle‐specific phenotypes. Previous reports have shown dysregulation of resting in vivo phosphorus metabolites under pathological conditions, including obesity, type 2 diabetes, spinal cord injury, and muscular dystrophy, and appear to be linked to clinical measures of glycemic control and body composition (Hooijmans et al, 2017; McCully, Mulcahy, Ryan, & Zhao, 2011; Ripley et al, 2018; Szendroedi et al, 2011). Specifically, resting phosphocreatine (PCr) levels have been shown to be negatively associated with HbA1c and fasting glucose levels, while heightened levels are linked with elevated intracellular ATP levels (Ripley et al, 2018).…”

“…Previous reports have shown dysregulation of resting in vivo phosphorus metabolites under pathological conditions, including obesity, type 2 diabetes, spinal cord injury, and muscular dystrophy, and appear to be linked to clinical measures of glycemic control and body composition (Hooijmans et al, 2017; McCully, Mulcahy, Ryan, & Zhao, 2011; Ripley et al, 2018; Szendroedi et al, 2011). Specifically, resting phosphocreatine (PCr) levels have been shown to be negatively associated with HbA1c and fasting glucose levels, while heightened levels are linked with elevated intracellular ATP levels (Ripley et al, 2018). Additionally, phosphodiester (PDE) content, a putative marker of skeletal muscle membrane damage, is elevated under conditions of lower muscle mass in spinal cord injury (McCully et al, 2011) and muscular dystrophy (Hooijmans et al, 2017).…”

“…Additionally, phosphodiester (PDE) content, a putative marker of skeletal muscle membrane damage, is elevated under conditions of lower muscle mass in spinal cord injury (McCully et al, 2011) and muscular dystrophy (Hooijmans et al, 2017). Furthermore, elevated PDE is associated with heightened HbA1c (Ripley et al, 2018; Szendroedi et al, 2011), reduced insulin sensitivity (Ripley et al, 2018; Szendroedi et al, 2011), increased body mass (Szendroedi et al, 2011), and elevated intramyocellular lipids (Ripley et al, 2018). Along with in vivo measures, biochemical analyses of muscle biospecimens have revealed an integral role of phosphorus metabolites in metabolic health.…”

Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy

“…In human patients with type II diabetes, ATP and ADP were measured in vivo in vastus lateralis [67]. Compared to age, sex, and BMI matched non-diabetic controls, diabetic patients display significantly less ATP, ADP, and PCr (phosphocreatine).…”