The Danger of Being Sedentary

Many awful consequences occur from being sedentary. Face it, over hundreds of thousands of years, our bodies were engineered to move. Many of the normal reparative, regenerative, and restorative processes that our body has are activated by physical activity. Otherwise, they lie dormant. Lactate, a critical signaling molecule, triggers robust beneficial reactions to an acute increase (from a low baseline) following exercise. However, chronically elevated lactate associated with metabolic diseases such as diabetes has significant negative consequences. Furthermore, the body doesn’t waste time maintaining critical energy systems and pathways if it doesn’t need them. These systems degrade and eventually serve as the trigger that initiates the presence of numerous metabolic disease states such as diabetes, cognitive decline, heart attack risk, stroke risk, fatty liver, and so on.

Until recently, we knew that being sedentary was bad for us… but we didn’t know how bad it was. Dr Inigo San-Millan recently published a paper comparing “healthy” but sedentary people to those who exercised moderately. The results were stunning.

The decrease in cellular respiration, mitochondrial function, the ability to utilize fat for energy, the ability to utilize lactate as fuel, and many more systems were dramatically diminished in the “healthy” cohort.

The bottom line is if you’re inactive, you’re not healthy. You’re harboring numerous metabolic disease states; you just don’t know it yet.

I have utilized an AI program to digest and discuss the article’s main points. Some of it is technical, but the overall message is critical to understand.

The article examined the key metabolic and cellular differences between sedentary and active individuals at rest and during exercise. The title is “Metabolic and Cellular Differences Between Sedentary and Active Individuals at Rest and During Exercise”:

Metabolic and Cellular Differences Between Sedentary and Active Individuals

The study by San-Millan et al. examines the metabolic and cellular differences between “healthy sedentary” individuals (SED) and moderately active individuals (AC), challenging the traditional notion of sedentary individuals as a healthy control group. The study focuses on skeletal muscle, a highly metabolically active organ, to investigate these differences both at rest and during exercise.

At Rest:

• Mitochondrial Respiration and Substrate Oxidation: SED individuals exhibited significantly reduced mitochondrial respiration, with decreases in complex I and II capacities, total electron system capacity, and electron system capacity coupled to ATP production via ATP synthase compared to AC individuals. [4, 8, 9] This indicates a lower capacity for energy production in sedentary individuals.
• Glucose Metabolism: While both groups had similar levels of GLUT4, the glucose transporter, SED individuals showed significantly decreased expression of the mitochondrial pyruvate carrier (MPC) and reduced pyruvate oxidation. [4, 19, 31, 32] This suggests that the downregulation of glucose metabolism may originate within the mitochondria, specifically at the pyruvate transport and oxidation stage, rather than at the cell membrane level.
• Fat Metabolism: SED individuals also displayed decreased mitochondrial fatty acid oxidation and reduced activity of carnitine palmitoyltransferase I (CPT1), a transporter responsible for moving fatty acids into mitochondria. [4, 22] This impaired ability to transport and oxidize fatty acids may contribute to the accumulation of intramuscular fat, which is associated with insulin resistance. [8-10, 22, 33]
• Cardiolipin (CL): Significant differences in CL content and composition were observed between the groups. AC individuals had greater total CL, a key phospholipid involved in mitochondrial structure and function. [13, 23] Additionally, AC individuals showed a significant increase in the percentage of tetralineolyl CL (L4CL), a specific type of CL linked to efficient fatty acid utilization by mitochondria. [13, 23, 34] These findings point to potential alterations in mitochondrial membrane integrity and function in SED individuals.
• Reactive Oxygen Species (ROS): While both groups produced ROS, a byproduct of mitochondrial activity, SED individuals exhibited higher ROS production normalized to oxygen flux, indicating a potentially leakier electron transport system and increased cellular stress. [12, 23]

During Exercise:

• Exercise Capacity: As anticipated, SED individuals demonstrated significantly lower absolute and relative VO2max (maximal oxygen uptake) and maximal power output compared to AC individuals, reflecting a reduced ability to perform aerobic exercise. [16, 24]
• Lactate Clearance Capacity: SED individuals had considerably higher blood lactate levels at the same power output as AC individuals, indicating a lower capacity for pyruvate oxidation and lactate clearance. [16, 25] This aligns with the findings from the resting studies, further supporting the idea of impaired mitochondrial pyruvate metabolism in sedentary individuals.
• Substrate Utilization: During exercise, SED individuals exhibited lower fat oxidation capacity compared to AC individuals, mirroring the observations from the resting studies regarding impaired fatty acid metabolism. [17, 25]
• Correlations Between Resting and Exercise Parameters: Robust correlations were found between resting mitochondrial parameters and exercise performance in both groups. [18, 26, 27, 35-38] For instance, fat oxidation during exercise was strongly correlated with resting mitochondrial fatty acid oxidation, while blood lactate levels during exercise were inversely correlated with resting mitochondrial pyruvate oxidation. These correlations suggest that the capacity for substrate utilization during exercise is closely linked to the underlying mitochondrial function at rest.

Overall, the study highlights that “healthy sedentary” individuals already display significant metabolic and cellular downregulations compared to moderately active individuals, both at rest and during exercise. These differences are observed across various aspects of mitochondrial function, including respiration, substrate oxidation, transporter activity, cardiolipin composition, and ROS production. Notably, the findings suggest that the impairment of glucose metabolism, characterized by reduced MPC expression and pyruvate oxidation, may precede the development of insulin resistance and GLUT4 dysregulation, challenging the traditional focus on these factors in the pathogenesis of type 2 diabetes.

The study also underscores the potential of using exercise testing, such as CPET and lactate, to assess mitochondrial function and predict the risk of developing metabolic diseases.